Protein targeting

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Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. [1] [2] [note 1] Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. [1] [2] Information contained in the protein itself directs this delivery process. [2] [3] Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases. [2] [4] [5]

Contents

History

Gunter Blobel, awarded the 1999 Nobel Prize in Physiology for his discovery that proteins contain intrinsic signal sequences. Gunter Blobel 2008 3.JPG
Günter Blobel, awarded the 1999 Nobel Prize in Physiology for his discovery that proteins contain intrinsic signal sequences.

In 1970, Günter Blobel conducted experiments on protein translocation across membranes. Blobel, then an assistant professor at Rockefeller University, built upon the work of his colleague George Palade. [6] Palade had previously demonstrated that non-secreted proteins were translated by free ribosomes in the cytosol, while secreted proteins (and target proteins, in general) were translated by ribosomes bound to the endoplasmic reticulum. [6] Candidate explanations at the time postulated a processing difference between free and ER-bound ribosomes, but Blobel hypothesized that protein targeting relied on characteristics inherent to the proteins, rather than a difference in ribosomes. Supporting his hypothesis, Blobel discovered that many proteins have a short amino acid sequence at one end that functions like a postal code specifying an intracellular or extracellular destination. [3] He described these short sequences (generally 13 to 36 amino acids residues) [1] as signal peptides or signal sequences and was awarded the 1999 Nobel prize in Physiology for the same. [7]

Signal peptides

Signal peptides serve as targeting signals, enabling cellular transport machinery to direct proteins to specific intracellular or extracellular locations. While no consensus sequence has been identified for signal peptides, many nonetheless possess a characteristic tripartite structure: [1]

  1. A positively charged, hydrophilic region near the N-terminal.
  2. A span of 10 to 15 hydrophobic amino acids near the middle of the signal peptide.
  3. A slightly polar region near the C-terminal, typically favoring amino acids with smaller side chains at positions approaching the cleavage site.

After a protein has reached its destination, the signal peptide is generally cleaved by a signal peptidase. [1] Consequently, most mature proteins do not contain signal peptides. While most signal peptides are found at the N-terminal, in peroxisomes the targeting sequence is located on the C-terminal extension. [8] Unlike signal peptides, signal patches are composed by amino acid residues that are discontinuous in the primary sequence but become functional when folding brings them together on the protein surface. [9] Unlike most signal sequences, signal patches are not cleaved after sorting is complete. [10] In addition to intrinsic signaling sequences, protein modifications like glycosylation can also induce targeting to specific intracellular or extracellular regions.

Protein translocation

Since the translation of mRNA into protein by a ribosome takes place within the cytosol, proteins destined for secretion or a specific organelle must be translocated. [11] This process can occur during translation, known as co-translational translocation, or after translation is complete, known as post-translational translocation. [12]

Co-translational translocation

A generalized overview of protein targeting that illustrates co-translational translocation to the endoplasmic reticulum and post-translational translocation to their specified locations. If no targeting sequence is present, then the synthesized protein will remain in the cytosol. General Overview of Protein Targeting.png
A generalized overview of protein targeting that illustrates co-translational translocation to the endoplasmic reticulum and post-translational translocation to their specified locations. If no targeting sequence is present, then the synthesized protein will remain in the cytosol.

Most secretory and membrane-bound proteins are co-translationally translocated. Proteins that reside in the endoplasmic reticulum (ER), golgi or endosomes also use the co-translational translocation pathway. This process begins while the protein is being synthesized on the ribosome, when a signal recognition particle (SRP) recognizes an N-terminal signal peptide of the nascent protein. [13] Binding of the SRP temporarily pauses synthesis while the ribosome-protein complex is transferred to an SRP receptor on the ER in eukaryotes, and the plasma membrane in prokaryotes. [14] There, the nascent protein is inserted into the translocon, a membrane-bound protein conducting channel composed of the Sec61 translocation complex in eukaryotes, and the homologous SecYEG complex in prokaryotes. [15] In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the membrane of the ER (eukaryotes) or plasma membrane (prokaryotes) by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold correctly.[ citation needed ] Once folded, the protein is modified as needed (for example, by glycosylation), then transported to the Golgi for further processing and goes to its target organelles or is retained in the ER by various ER retention mechanisms.

The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. These proteins are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor or signal-anchor sequence. [16] These complex membrane proteins are currently characterized using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit this model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genes in humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This translocation, which has been demonstrated with opsin with in vitro experiments, [17] [18] breaks the usual pattern of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.

Post-translational translocation

Even though most secretory proteins are co-translationally translocated, some are translated in the cytosol and later transported to the ER/plasma membrane by a post-translational system. In prokaryotes this process requires certain cofactors such as SecA and SecB and is facilitated by Sec62 and Sec63, two membrane-bound proteins. [19] The Sec63 complex, which is embedded in the ER membrane, causes hydrolysis of ATP, allowing chaperone proteins to bind to an exposed peptide chain and slide the polypeptide into the ER lumen. Once in the lumen the polypeptide chain can be folded properly. This process only occurs in unfolded proteins located in the cytosol. [20]

In addition, proteins targeted to other cellular destinations, such as mitochondria, chloroplasts, or peroxisomes, use specialized post-translational pathways. Proteins targeted for the nucleus are also translocated post-translationally through the addition of a nuclear localization signal (NLS) that promotes passage through the nuclear envelope via nuclear pores. [21]

Sorting of proteins

Mitochondria

Overview of the major protein import pathways of mitochondria. Overview of proteins targeted to the mitochondira.png
Overview of the major protein import pathways of mitochondria.
The carrier pathway for proteins targeted to the mitochondrial inner membrane. Carrier pathway for proteins to inner membrane.png
The carrier pathway for proteins targeted to the mitochondrial inner membrane.

While some proteins in the mitochondria originate from mitochondrial DNA within the organelle, most mitochondrial proteins are synthesized as cytosolic precursors containing uptake peptide signals. [22] [23] [24] [25] Unfolded proteins bound by cytosolic chaperone hsp70 that are targeted to the mitochondria may be localized to four different areas depending on their sequences. [2] [25] [26] They may be targeted to the mitochondrial matrix, the outer membrane, the intermembrane space, or the inner membrane. Defects in any one or more of these processes has been linked to health and disease. [27]

Mitochondrial matrix

Proteins destined for the mitochondrial matrix have specific signal sequences at their beginning (N-terminus) that consist of a string of 20 to 50 amino acids. These sequences are designed to interact with receptors that guide the proteins to their correct location inside the mitochondria. The sequences have a unique structure with clusters of water-loving (hydrophilic) and water-avoiding (hydrophobic) amino acids, giving them a dual nature known as amphipathic. These amphipathic sequences typically form a spiral shape (alpha-helix) with the charged amino acids on one side and the hydrophobic ones on the opposite side. This structural feature is essential for the sequence to function correctly in directing proteins to the matrix. If mutations occur that mess with this dual nature, the protein often fails to reach its intended destination, although not all changes to the sequence have this effect. This indicates the importance of the amphipathic property for the protein to be correctly targeted to the mitochondrial matrix. [28]

The pre-sequence pathway into the mitochondrial inner membrane (IM) and mitochondrial matrix. Inner membrane and matrix protein targeting.png
The pre-sequence pathway into the mitochondrial inner membrane (IM) and mitochondrial matrix.

Proteins targeted to the mitochondrial matrix first involves interactions between the matrix targeting sequence located at the N-terminus and the outer membrane import receptor complex TOM20/22. [2] [23] [29] In addition to the docking of internal sequences and cytosolic chaperones to TOM70. [2] [23] [29] Where TOM is an abbreviation for translocase of the outer membrane. Binding of the matrix targeting sequence to the import receptor triggers a handoff of the polypeptide to the general import core (GIP) known as TOM40. [2] [23] [29] The general import core (TOM40) then feeds the polypeptide chain through the intermembrane space and into another translocase complex TIM17/23/44 located on the inner mitochondrial membrane. [2] [24] [25] [30] This is accompanied by the necessary release of the cytosolic chaperones that maintain an unfolded state prior to entering the mitochondria. As the polypeptide enters the matrix, the signal sequence is cleaved by a processing peptidase and the remaining sequences are bound by mitochondrial chaperones to await proper folding and activity. [25] [26] The push and pull of the polypeptide from the cytosol to the intermembrane space and then the matrix is achieved by an electrochemical gradient that is established by the mitochondrion during oxidative phosphorylation. [1] [24] [25] [26] In which a mitochondrion active in metabolism has generated a negative potential inside the matrix and a positive potential in the intermembrane space. [25] [31] It is this negative potential inside the matrix that directs the positively charged regions of the targeting sequence into its desired location.

Mitochondrial inner membrane

Targeting of mitochondrial proteins to the inner membrane may follow 3 different pathways depending upon their overall sequences, however, entry from the outer membrane remains the same using the import receptor complex TOM20/22 and TOM40 general import core. [2] [24] The first pathway for proteins targeted to the inner membrane follows the same steps as those designated to the matrix where it contains a matrix targeting sequence that channels the polypeptide to the inner membrane complex containing the previously mentioned translocase complex TIM17/23/44. [2] [24] [25] However, the difference is that the peptides that are designated to the inner membrane and not the matrix contain an upstream sequence called the stop-transfer-anchor sequence. [2] This stop-transfer-anchor sequence is a hydrophobic region that embeds itself into the phospholipid bilayer of the inner membrane and prevents translocation further into the mitochondrion. [24] [25] The second pathway for proteins targeted to the inner membrane follows the matrix localization pathway in its entirety. However, instead of a stop-transfer-anchor sequence, it contains another sequence that interacts with an inner membrane protein called Oxa-1 once inside the matrix that will embed it into the inner membrane. [2] [24] [25] The third pathway for mitochondrial proteins targeted to the inner membrane follow the same entry as the others into the outer membrane, however, this pathway utilizes the translocase complex TIM22/54 assisted by complex TIM9/10 in the intermembrane space to anchor the incoming peptide into the membrane. [2] [24] [25] The peptides for this last pathway do not contain a matrix targeting sequence, but instead contain several internal targeting sequences.

Mitochondrial intermembrane space

If instead the precursor protein is designated to the intermembrane space of the mitochondrion, there are two pathways this may occur depending on the sequences being recognized. The first pathway to the intermembrane space follows the same steps for an inner membrane targeted protein. However, once bound to the inner membrane the C-terminus of the anchored protein is cleaved via a peptidase that liberates the preprotein into the intermembrane space so it can fold into its active state. [2] [25] One of the greatest examples for a protein that follows this pathway is cytochrome b2, that upon being cleaved will interact with a heme cofactor and become active. [2] [32] The second intermembrane space pathway does not utilize any inner membrane complexes and therefor does not contain a matrix targeting signal. Instead, it enters through the general import core TOM40 and is further modified in the intermembrane space to achieve its active conformation. TIM9/10 is an example of a protein that follows this pathway in order to be in the location it needs to be to assist in inner membrane targeting. [2] [25] [33]

Mitochondrial outer membrane

Outer membrane targeting simply involves the interaction of precursor proteins with the outer membrane translocase complexes that embeds it into the membrane via internal-targeting sequences that are to form hydrophobic alpha helices or beta barrels that span the phospholipid bilayer. [2] [24] [25] This may occur by two different routes depending on the preprotein internal sequences. If the preprotein contains internal hydrophobic regions capable of forming alpha helices, then the preprotein will utilize the mitochondrial import complex (MIM) and be transferred laterally to the membrane. [24] [25] For preproteins containing hydrophobic internal sequences that correlate to beta-barrel forming proteins, they will be imported from the aforementioned outer membrane complex TOM20/22 to the intermembrane space. In which they will interact with TIM9/10 intermembrane-space protein complex that transfers them to sorting and assembly machinery (SAM) that is present in the outer membrane that laterally displaces the targeted protein as a beta-barrel. [24] [25]

Chloroplasts

Chloroplasts are similar to mitochondria in that they contain their own DNA for production of some of their components. However, the majority of their proteins are obtained via post-translational translocation and arise from nuclear genes. Proteins may be targeted to several sites of the chloroplast depending on their sequences such as the outer envelope, inner envelope, stroma, thylakoid lumen, or the thylakoid membrane. [2] Proteins are targeted to Thylakoids by mechanisms related to Bacterial Protein Translocation. [28] Proteins targeted to the envelope of chloroplasts usually lack cleavable sorting sequence and are laterally displaced via membrane sorting complexes. General import for the majority of preproteins requires translocation from the cytosol through the Toc and Tic complexes located within the chloroplast envelope. Where Toc is an abbreviation for the translocase of the outer chloroplast envelope and Tic is the translocase of the inner chloroplast envelope. There is a minimum of three proteins that make up the function of the Toc complex. Two of which, referred to as Toc159 and Toc34, are responsible for the docking of stromal import sequences and both contain GTPase activity. The third known as Toc 75, is the actual translocation channel that feeds the recognized preprotein by Toc159/34 into the chloroplast. [34]

Stroma

Targeting to the stroma requires the preprotein to have a stromal import sequence that is recognized by the Tic complex of the inner envelope upon being translocated from the outer envelope by the Toc complex. The Tic complex is composed of at least five different Tic proteins that are required to form the translocation channel across the inner envelope. [35] Upon being delivered to the stroma, the stromal import sequence is cleaved off via a signal peptidase. This delivery process to the stroma is currently known to be driven by ATP hydrolysis via stromal HSP chaperones, instead of the transmembrane electrochemical gradient that is established in mitochondria to drive protein import. [34] Further intra-chloroplast sorting depends on additional target sequences such as those designated to the thylakoid membrane or the thylakoid lumen.

Thylakoid lumen

If a protein is to be targeted to the thylakoid lumen, this may occur via four differently known routes that closely resemble bacterial protein transport mechanisms. The route that is taken depends upon the protein delivered to the stroma being in either an unfolded or metal-bound folded state. Both of which will still contain a thylakoid targeting sequence that is also cleaved upon entry to the lumen. While protein import into the stroma is ATP-driven, the pathway for metal-bound proteins in a folded state to the thylakoid lumen has been shown to be driven by a pH gradient.

Pathways for proteins targeted to the thylakoid membrane in chloroplasts. Protein targeting to the thylakoid membrane in chloroplasts.png
Pathways for proteins targeted to the thylakoid membrane in chloroplasts.

Thylakoid membrane

Proteins bound for the membrane of the thylakoid will follow up to four known routes that are illustrated in the corresponding figure shown. They may follow a co-translational insertion route that utilizes stromal ribosomes and the SecY/E transmembrane complex, the SRP-dependent pathway, the spontaneous insertion pathway, or the GET pathway. The last of the three are post-translational pathways originating from nuclear genes and therefor constitute the majority of proteins targeted to the thylakoid membrane. According to recent review articles in the journal of biochemistry and molecular biology, the exact mechanisms are not yet fully understood.

Both chloroplasts and mitochondria

Many proteins are needed in both mitochondria and chloroplasts. [36] In general the dual-targeting peptide is of intermediate character to the two specific ones. The targeting peptides of these proteins have a high content of basic and hydrophobic amino acids, a low content of negatively charged amino acids. They have a lower content of alanine and a higher content of leucine and phenylalanine. The dual targeted proteins have a more hydrophobic targeting peptide than both mitochondrial and chloroplastic ones. However, it is tedious to predict if a peptide is dual-targeted or not based on its physio-chemical characteristics.

Nucleus

The nucleus of a cell is surrounded by a nuclear envelope consisting of two layers, with the inner layer providing structural support and anchorage for chromosomes and the nuclear lamina. [16] The outer layer is similar to the endoplasmic reticulum (ER) membrane. This envelope contains nuclear pores, which are complex structures made from around 30 different proteins. [16] These pores act as selective gates that control the flow of molecules into and out of the nucleus.

While small molecules can pass through these pores without issue, larger molecules, like RNA and proteins destined for the nucleus, must have specific signals to be allowed through. [20] These signals are known as nuclear localization signals, usually comprising short sequences rich in positively charged amino acids like lysine or arginine. [16]

Proteins called nuclear import receptors recognize these signals and guide the large molecules through the nuclear pores by interacting with the disordered, mesh-like proteins that fill the pore. [16] The process is dynamic, with the receptor moving the molecule through the meshwork until it reaches the nucleus. [20]

Once inside, a GTPase enzyme called Ran, which can exist in two different forms (one bound to GTP and the other to GDP), facilitates the release of the cargo inside the nucleus and recycles the receptor back to the cytosol. [16] [20] The energy for this transport comes from the hydrolysis of GTP by Ran. Similarly, nuclear export receptors help move proteins and RNA out of the nucleus using a different signal and also harnessing Ran's energy conversion. [16]

Overall, the nuclear pore complex works efficiently to transport macromolecules at high speed, allowing proteins to move in their folded state and ribosomal components as complete particles, which is distinct from how proteins are transported into most other organelles. [16]

Endoplasmic reticulum

The endoplasmic reticulum (ER) plays a key role in protein synthesis and distribution in eukaryotic cells. It's a vast network of membranes where proteins are processed and sorted to various destinations, including the ER itself, the cell surface, and other organelles like the Golgi apparatus, endosomes, and lysosomes. [16] Unlike other organelle-targeted proteins, those headed for the ER start to be transferred across its membrane while they're still being made. [20] [16]

Protein synthesis and sorting

There are two types of proteins that move to the ER: water-soluble proteins, which completely cross into the ER lumen, and transmembrane proteins, which partly cross and embed themselves within the ER membrane. [20] These proteins find their way to the ER with the help of an ER signal sequence, a short stretch of hydrophobic amino acids. [16]

Proteins entering the ER are synthesized by ribosomes. There are two sets of ribosomes in the cell: those bound to the ER (making it look 'rough') and those floating freely in the cytosol. Both sets are identical but differ in the proteins they synthesize at a given moment. [16] [20] Ribosomes that are making proteins with an ER signal sequence attach to the ER membrane and start the translocation process. This process is energy-efficient because the growing protein chain itself pushes through the ER membrane as it elongates. [16]

As the mRNA is translated into a protein, multiple ribosomes may attach to it, creating a structure called a polyribosome. [16] If the mRNA is coding for a protein with an ER signal sequence, the polyribosome attaches to the ER membrane, and the protein begins to enter the ER while it is still being synthesized. [20] [16]

Guided entry of soluble proteins

In the process of protein synthesis within eukaryotic cells, soluble proteins that are destined for the endoplasmic reticulum (ER) or for secretion out of the cell are guided to the ER by a two-part system. Firstly, a signal-recognition particle (SRP) in the cytosol attaches to the emerging protein's ER signal sequence and the ribosome itself. [16] Secondly, an SRP receptor located in the ER membrane recognizes and binds to the SRP. This interaction temporarily slows down protein synthesis until the SRP and ribs complex binds to the SRP receptor on the ER. [16] [20]

Once this binding occurs, the SRP is released, and the ribosome is transferred to a protein translocator in the ER membrane, allowing protein synthesis to continue. [16] [20] The polypeptide chain of the protein is then threaded through a channel in the translocator into the ER lumen. The signal sequence of the protein, typically at the beginning (N-terminus) of the polypeptide chain, plays a dual role. It not only targets the ribosome to the ER but also triggers the opening of the translocator. [16] As the protein is fed through the translocator, the signal sequence stays attached, allowing the rest of the protein to move through as a loop. A signal peptidase inside the ER then cuts off the signal sequence, which is subsequently discarded into the lipid bilayer of the ER membrane and broken down. [16] [20]

Finally, once the last part of the protein (the C-terminus) passes through the translocator, the entire soluble protein is released into the ER lumen, where it can then fold and undergo further modifications or be transported to its final destination. [16] [20]

Mechanisms of transmembrane protein integration

Transmembrane proteins, which are partly integrated into the ER membrane rather than released into the ER lumen, have a complex assembly process. [16] [20] The initial stages are similar to soluble proteins: a signal sequence starts the insertion into the ER membrane. However, this process is interrupted by a stop-transfer sequence—a string of hydrophobic amino acids—which causes the translocator to halt and release the protein laterally into the membrane. [16] [20] This results in a single-pass transmembrane protein with one end inside the ER lumen and the other in the cytosol, and this orientation is permanent. [16]

Some transmembrane proteins use an internal signal (start-transfer sequence) instead of one at the N-terminus, and unlike the initial signal sequence, this start-transfer sequence isn't removed. [16] [20] It begins the transfer process, which continues until a stop-transfer sequence is encountered, at which point both sequences become anchored in the membrane as alpha-helical segments. [16]

In more complex proteins that span the membrane multiple times, additional pairs of start- and stop-transfer sequences are used to weave the protein into the membrane in a fashion akin to a sewing machine. Each pair allows a new segment to cross the membrane and adds to the protein's structure, ensuring it is properly embedded with the correct arrangement of segments inside and outside the ER membrane. [16]

Peroxisomes

Generalized Protein Targeting to the Peroxisomal Matrix Peroxisome Protein Targeting.png
Generalized Protein Targeting to the Peroxisomal Matrix

Peroxisomes contain a single phospholipid bilayer that surrounds the peroxisomal matrix containing a wide variety of proteins and enzymes that participate in anabolism and catabolism. Peroxisomes are specialized cell organelles that carry out specific oxidative reactions using molecular oxygen. Their primary function is to remove hydrogen atoms from organic molecules, a process that results in the production of hydrogen peroxide (H2O2). [37] [20] Within peroxisomes, an enzyme called catalase plays a critical role. It uses the hydrogen peroxide generated in the earlier reaction to oxidize various other substances, including phenols, formic acid, formaldehyde, and alcohol. [37] [20] This is known as the "peroxidative" reaction. [20]

Peroxisomes are particularly important in liver and kidney cells for detoxifying harmful substances that enter the bloodstream. For example, they are responsible for oxidizing about 25% of the ethanol we consume into acetaldehyde. [37] Additionally, catalase within peroxisomes can break down excess hydrogen peroxide into water and oxygen and thus preventing potential damage from the build-up of H2O2. [37] [20] Since it contains no internal DNA like that of the mitochondria or chloroplast all peroxisomal proteins are encoded by nuclear genes. [38] To date there are two types of known Peroxisome Targeting Signals (PTS):

  1. Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine-lysine-leucine (SKL). [37] The initial research that led to the discovery of this consensus observed that when firefly luciferase was expressed in cultured insect cells it was targeted to the peroxisome. By testing a variety of mutations in the gene encoding the expressed luciferase, the consensus sequence was then determined. [39] It has also been found that by adding this C-terminal sequence of SKL to a cytosolic protein that it becomes targeted for transport to the peroxisome. The majority of peroxisomal matrix proteins possess this PTS1 type signal.
  2. Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid). [37]

There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them. [40]

In the case of cytosolic proteins that are produced with the PTS1 C-terminal sequence, its path to the peroxisomal matrix is dependent upon binding to another cytosolic protein called pex5 (peroxin 5). [41] Once bound, pex5 interacts with a peroxisomal membrane protein pex14 to form a complex. When the pex5 protein with bound cargo interacts with the pex14 membrane protein, the complex induces the release of the targeted protein into the matrix. Upon releasing the cargo protein into the matrix, pex5 dissociation from pex14 occurs via ubiquitinylation by a membrane complex comprising pex2, pex12, and pex10 followed by an ATP dependent removal involving the cytosolic protein complex pex1 and pex6. [42] The cycle for pex5 mediated import into the peroxisomal matrix is restored after the ATP dependent removal of ubiquitin and is free to bind with another protein containing a PTS1 sequence. [41] Proteins containing a PTS2 targeting sequence are mediated by a different cytosolic protein but are believed to follow a similar mechanism to that of those containing the PTS1 sequence. [37]

Diseases

Protein transport is defective in the following genetic diseases:

In bacteria and archaea

As discussed above (see protein translocation), most prokaryotic membrane-bound and secretory proteins are targeted to the plasma membrane by either a co-translation pathway that uses bacterial SRP or a post-translation pathway that requires SecA and SecB. At the plasma membrane, these two pathways deliver proteins to the SecYEG translocon for translocation. Bacteria may have a single plasma membrane (Gram-positive bacteria), or an inner membrane plus an outer membrane separated by the periplasm (Gram-negative bacteria). Besides the plasma membrane the majority of prokaryotes lack membrane-bound organelles as found in eukaryotes, but they may assemble proteins onto various types of inclusions such as gas vesicles and storage granules.

Gram-negative bacteria

In gram-negative bacteria proteins may be incorporated into the plasma membrane, the outer membrane, the periplasm or secreted into the environment. Systems for secreting proteins across the bacterial outer membrane may be quite complex and play key roles in pathogenesis. These systems may be described as type I secretion, type II secretion, etc.

Gram-positive bacteria

In most gram-positive bacteria, certain proteins are targeted for export across the plasma membrane and subsequent covalent attachment to the bacterial cell wall. A specialized enzyme, sortase, cleaves the target protein at a characteristic recognition site near the protein C-terminus, such as an LPXTG motif (where X can be any amino acid), then transfers the protein onto the cell wall. Several analogous systems are found that likewise feature a signature motif on the extra-cytoplasmic face, a C-terminal transmembrane domain, and cluster of basic residues on the cytosolic face at the protein's extreme C-terminus. The PEP-CTERM/exosortase system, found in many Gram-negative bacteria, seems to be related to extracellular polymeric substance production. The PGF-CTERM/archaeosortase A system in archaea is related to S-layer production. The GlyGly-CTERM/rhombosortase system, found in the Shewanella, Vibrio, and a few other genera, seems involved in the release of proteases, nucleases, and other enzymes.

Bioinformatic tools

Notes

  1. ↑ This article deals with protein targeting in eukaryotes unless specified otherwise

See also

Related Research Articles

<span class="mw-page-title-main">Endoplasmic reticulum</span> Cell organelle that synthesizes, folds and processes proteins

The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

<span class="mw-page-title-main">Transmembrane protein</span> Protein spanning across a biological membrane

A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently undergo significant conformational changes to move a substance through the membrane. They are usually highly hydrophobic and aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them (beta-barrels) can be also extracted using denaturing agents.

<span class="mw-page-title-main">Thylakoid</span> Membrane enclosed compartments in chloroplasts and cyanobacteria

Thylakoids are membrane-bound compartments inside chloroplasts and cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. Thylakoids consist of a thylakoid membrane surrounding a thylakoid lumen. Chloroplast thylakoids frequently form stacks of disks referred to as grana. Grana are connected by intergranal or stromal thylakoids, which join granum stacks together as a single functional compartment.

The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes.

A signal peptide is a short peptide present at the N-terminus of most newly synthesized proteins that are destined toward the secretory pathway. These proteins include those that reside either inside certain organelles, secreted from the cell, or inserted into most cellular membranes. Although most type I membrane-bound proteins have signal peptides, most type II and multi-spanning membrane-bound proteins are targeted to the secretory pathway by their first transmembrane domain, which biochemically resembles a signal sequence except that it is not cleaved. They are a kind of target peptide.

The translocon is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transports nascent polypeptides with a targeting signal sequence into the interior space of the endoplasmic reticulum (ER) from the cytosol. This translocation process requires the protein to cross a hydrophobic lipid bilayer. The same complex is also used to integrate nascent proteins into the membrane itself. In prokaryotes, a similar protein complex transports polypeptides across the (inner) plasma membrane or integrates membrane proteins. In either case, the protein complex are formed from Sec proteins, with the heterotrimeric Sec61 being the channel. In prokaryotes, the homologous channel complex is known as SecYEG.

The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amine group is bonded to the carboxylic group of another amino acid, making it a chain. That leaves a free carboxylic group at one end of the peptide, called the C-terminus, and a free amine group on the other end called the N-terminus. By convention, peptide sequences are written N-terminus to C-terminus, left to right (in LTR writing systems). This correlates the translation direction to the text direction, because when a protein is translated from messenger RNA, it is created from the N-terminus to the C-terminus, as amino acids are added to the carboxyl end of the protein.

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

<span class="mw-page-title-main">Intermembrane space</span> Part of a cell

The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the inner membrane and the outer membrane of a mitochondrion or a chloroplast. It also refers to the space between the inner and outer nuclear membranes of the nuclear envelope, but is often called the perinuclear space. The IMS of mitochondria plays a crucial role in coordinating a variety of cellular activities, such as regulation of respiration and metabolic functions. Unlike the IMS of the mitochondria, the IMS of the chloroplast does not seem to have any obvious function.

A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides. Secretory proteins are synthesized in the endoplasmic reticulum.

<span class="mw-page-title-main">TIM/TOM complex</span>

The TIM/TOM complex is a protein complex in cellular biochemistry which translocates proteins produced from nuclear DNA through the mitochondrial membrane for use in oxidative phosphorylation. In enzymology, the complex is described as an mitochondrial protein-transporting ATPase, or more systematically ATP phosphohydrolase , as the TIM part requires ATP hydrolysis to work.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">Mitochondrial carrier</span>

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.

<span class="mw-page-title-main">Signal recognition particle RNA</span>

The signal recognition particle RNA, is part of the signal recognition particle (SRP) ribonucleoprotein complex. SRP recognizes the signal peptide and binds to the ribosome, halting protein synthesis. SRP-receptor is a protein that is embedded in a membrane, and which contains a transmembrane pore. When the SRP-ribosome complex binds to SRP-receptor, SRP releases the ribosome and drifts away. The ribosome resumes protein synthesis, but now the protein is moving through the SRP-receptor transmembrane pore.

<span class="mw-page-title-main">Mitochondrial antiviral-signaling protein</span> Protein-coding gene in the species Homo sapiens

Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.

<span class="mw-page-title-main">Translocase of the outer membrane</span>

The translocase of the outer membrane (TOM) is a complex of proteins found in the outer mitochondrial membrane of the mitochondria. It allows movement of proteins through this barrier and into the intermembrane space of the mitochondrion. Most of the proteins needed for mitochondrial function are encoded by the nucleus of the cell. The outer membrane of the mitochondrion is impermeable to large molecules greater than 5000 daltons. The TOM works in conjunction with the translocase of the inner membrane (TIM) to translocate proteins into the mitochondrion. Many of the proteins in the TOM complex, such as TOMM22, were first identified in Neurospora crassa and Saccharomyces cerevisiae. Many of the genes encoding these proteins are designated as TOMM (translocase of the outer mitochondrial membrane) complex genes.

<span class="mw-page-title-main">Chloroplast DNA</span> DNA located in cellular organelles called chloroplasts

Chloroplast DNA (cpDNA) is the DNA located in chloroplasts, which are photosynthetic organelles located within the cells of some eukaryotic organisms. Chloroplasts, like other types of plastid, contain a genome separate from that in the cell nucleus. The existence of chloroplast DNA was identified biochemically in 1959, and confirmed by electron microscopy in 1962. The discoveries that the chloroplast contains ribosomes and performs protein synthesis revealed that the chloroplast is genetically semi-autonomous. The first complete chloroplast genome sequences were published in 1986, Nicotiana tabacum (tobacco) by Sugiura and colleagues and Marchantia polymorpha (liverwort) by Ozeki et al. Since then, a great number of chloroplast DNAs from various species have been sequenced.

A target peptide is a short peptide chain that directs the transport of a protein to a specific region in the cell, including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome and plasma membrane. Some target peptides are cleaved from the protein by signal peptidases after the proteins are transported.

<span class="mw-page-title-main">TIC/TOC complex</span>

The TIC and TOC complexes are translocons located in the chloroplast of a eukaryotic cell, that is, protein complexes that facilitate the transfer of proteins in and out through the chloroplast's membrane. It mainly transports proteins made in the cytoplasm into the chloroplast. The TIC complex(translocon on the inner chloroplast membrane) is located in the inner envelope of the chloroplast. The TOC complex(translocon on the outer chloroplast membrane) is located in the outer envelope of the chloroplast.

<span class="mw-page-title-main">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

References

  1. 1 2 3 4 5 6 Nelson DL (January 2017). Lehninger principles of biochemistry. Cox, Michael M.,, Lehninger, Albert L. (Seventh ed.). New York, NY. ISBN   978-1-4641-2611-6. OCLC   986827885.{{cite book}}: CS1 maint: location missing publisher (link)
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Lodish, Berk, Kaiser, Krieger, Bretscher, Ploegh, Martin, Yaffe, Amon (2021). Molecular Cell Biology (9th ed.). New York, NY: W.H. Freeman and Company. ISBN   978-1-319-20852-3.{{cite book}}: CS1 maint: multiple names: authors list (link)
  3. 1 2 Blobel G, Dobberstein B (December 1975). "Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma". The Journal of Cell Biology. 67 (3): 835–51. doi:10.1083/jcb.67.3.835. PMC   2111658 . PMID   811671.
  4. 1 2 Schmidt V, Willnow TE (February 2016). "Protein sorting gone wrong--VPS10P domain receptors in cardiovascular and metabolic diseases". Atherosclerosis. 245: 194–9. doi: 10.1016/j.atherosclerosis.2015.11.027 . PMID   26724530.
  5. ↑ Guo Y, Sirkis DW, Schekman R (2014-10-11). "Protein sorting at the trans-Golgi network". Annual Review of Cell and Developmental Biology. 30 (1): 169–206. doi:10.1146/annurev-cellbio-100913-013012. PMID   25150009.
  6. 1 2 Leslie M (August 2005). "Lost in translation: the signal hypothesis". The Journal of Cell Biology. 170 (3): 338. doi:10.1083/jcb1703fta1. PMC   2254867 . PMID   16167405.
  7. ↑ "The Nobel Prize in Physiology or Medicine 1999". NobelPrize.org. Retrieved 2020-09-19.
  8. ↑ Wanders RJ (May 2004). "Metabolic and molecular basis of peroxisomal disorders: a review". American Journal of Medical Genetics. Part A. 126A (4): 355–75. doi:10.1002/ajmg.a.20661. PMID   15098234. S2CID   24025032.
  9. ↑ Moreira IS, Fernandes PA, Ramos MJ (September 2007). "Hot spots--a review of the protein-protein interface determinant amino-acid residues". Proteins. 68 (4): 803–12. doi: 10.1002/prot.21396 . PMID   17546660. S2CID   18578313.
  10. ↑ Suzanne R. Pfeffer; James E. Rothman (1 January 1987). "Biosynthetic protein transport and sorting by the endoplasmic reticulum and Golgi". Annual Review of Biochemistry . 56: 829–852. doi:10.1146/ANNUREV.BI.56.070187.004145. ISSN   0066-4154. PMID   3304148. Wikidata   Q39664981.
  11. ↑ Sommer MS, Schleiff E (August 2014). "Protein targeting and transport as a necessary consequence of increased cellular complexity". Cold Spring Harbor Perspectives in Biology. 6 (8): a016055. doi:10.1101/cshperspect.a016055. PMC   4107987 . PMID   25085907.
  12. ↑ Walter P, Ibrahimi I, Blobel G (November 1981). "Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein". The Journal of Cell Biology. 91 (2 Pt 1): 545–50. doi:10.1083/jcb.91.2.545. PMC   2111968 . PMID   7309795.
  13. ↑ Voorhees RM, Hegde RS (August 2016). "Toward a structural understanding of co-translational protein translocation". Current Opinion in Cell Biology. 41: 91–9. doi:10.1016/j.ceb.2016.04.009. PMID   27155805.
  14. ↑ Nyathi Y, Wilkinson BM, Pool MR (November 2013). "Co-translational targeting and translocation of proteins to the endoplasmic reticulum". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (11): 2392–402. doi: 10.1016/j.bbamcr.2013.02.021 . PMID   23481039.
  15. ↑ Mandon EC, Trueman SF, Gilmore R (August 2009). "Translocation of proteins through the Sec61 and SecYEG channels". Current Opinion in Cell Biology. 21 (4): 501–7. doi:10.1016/j.ceb.2009.04.010. PMC   2916700 . PMID   19450960.
  16. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Alberts (November 2018). Essential cell biology (Fifth ed.). New York. ISBN   978-0-393-67953-3. OCLC   1048014962.{{cite book}}: CS1 maint: location missing publisher (link)
  17. ↑ Kanner EM, Friedlander M, Simon SM. (2003). "Co-translational targeting and translocation of the amino terminus of opsin across the endoplasmic membrane requires GTP but not ATP". J. Biol. Chem. 278 (10): 7920–7926. doi : 10.1074/jbc.M207462200. PMID   12486130.
  18. ↑ Kanner EM, Klein IK. et al. (2002). "The amino terminus of opsin translocates "posttranslationally" as efficiently as cotranslationally". Biochemistry 41 (24): 7707–7715. doi : 10.1021/bi0256882. PMID   12056902.
  19. ↑ Rapoport TA (November 2007). "Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes". Nature. 450 (7170): 663–9. Bibcode:2007Natur.450..663R. doi:10.1038/nature06384. PMID   18046402. S2CID   2497138.
  20. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Lodish H, Berk A, Kaiser C, Krieger M, Bretscher A, Ploegh H, Amon A, Martin K (2008). Molecular Cell Biology (8th ed.). New York: W.H. Freeman and Company. pp. 591–592. ISBN   978-1-4641-8339-3.
  21. ↑ Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (February 2007). "Classical nuclear localization signals: definition, function, and interaction with importin alpha". The Journal of Biological Chemistry. 282 (8): 5101–5. doi: 10.1074/jbc.R600026200 . PMC   4502416 . PMID   17170104.
  22. ↑ Cox M, Doudna J, O'Donnel M (2015). Molecular Biology Principles and Practice (2nd ed.). New York, NY: W.H. Freeman and Company. ISBN   978-1-319-15413-4.{{cite book}}: CS1 maint: multiple names: authors list (link)
  23. 1 2 3 4 Araiso Y, Endo T (2022). "Structural overview of the translocase of the mitochondrial outer membrane complex". Biophys Physicobiol. 19: e190022. doi:10.2142/biophysico.bppb-v19.0022. PMC   9260164 . PMID   35859989.
  24. 1 2 3 4 5 6 7 8 9 10 11 Eaglesfield R, Tokatlidis K (2021). "Targeting and Insertion of Membrane Proteins in Mitochondria". Frontiers in Cell and Developmental Biology. 9: 803205. doi: 10.3389/fcell.2021.803205 . PMC   8740019 . PMID   35004695 – via Frontiers.
  25. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Wiedemann N, Pfanner N (2017). "Mitochondrial Machineries for Protein Import and Assembly". Annual Review of Biochemistry. 86: 685–714. doi: 10.1146/annurev-biochem-060815-014352 . PMID   28301740 – via Ann Rev Biochem Online.
  26. 1 2 3 Truscott K, Pfanner N, Voos W (2001). "Transport of proteins into mitochondria". Reviews of Physiology, Biochemistry and Pharmacology. 143: 81–136. doi:10.1007/BFb0115593. ISBN   978-3-540-41474-2. PMID   11428265.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Kang Y, Fielden L, Stojanovski D (2018). "Mitochondrial protein transport in health and disease". Seminars in Cell & Developmental Biology. 76: 142–153. doi:10.1016/j.semcdb.2017.07.028. PMID   28765093.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. 1 2 Lodish, Harvey; Berk, Arnold; Kaiser, Chris A; Krieger, Monty; Bretscher, Anthony; Ploegh, Hidde; Amon, Angelika; Scott, Matthew P (2016). Molecular Cell Biology (8th ed.). New York, USA: W.H. Freeman and Company. pp. 609–610. ISBN   978-1-4641-8339-3.
  29. 1 2 3 Pfanner N, Geissler A (2001). "Versatility of the mitochondrial protein import machinery". Nature Reviews Molecular Cell Biology. 2 (5): 339–349. doi:10.1038/35073006. PMID   11331908. S2CID   21011113 – via Nature.
  30. 1 2 Bauer M, Hofmann S, Neupert W, Brunner M (2000). "Protein translocation into mitochondria: the role of TIM complexes". Trends in Cell Biology. 10 (1): 25–31. doi:10.1016/S0962-8924(99)01684-0. PMID   10603473 – via Elsevier Science Direct.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ↑ Nelson D, Cox M (2017). Principles of Biochemistry (7th ed.). New York, NY: W.H. Freeman and Company. ISBN   978-1-4641-2611-6.
  32. ↑ Shwarz E, Seytter T, Guiard B, Neupert W (1993). "Targeting of cytochrome b2 into the mitochondrial intermembrane space: specific recognition of the sorting signal". EMBO J. 12– via PubMed.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ↑ Kurz M, Martin H, Rassow J, Pfanner N, Ryan M (2017). "Biogenesis of Tim Proteins of the Mitochondrial Carrier Import Pathway: Differential Targeting Mechanisms and Crossing Over with the Main Import Pathway". Molecular Biology of the Cell. 10 (7): 2461–2474. doi:10.1091/mbc.10.7.2461. PMC   25469 . PMID   10397776.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  34. 1 2 Soll J, Schleiff E (2004). "Protein import into chloroplasts". Nature Reviews Molecular Cell Biology. 5 (3): 198–208. doi:10.1038/nrm1333. PMID   14991000. S2CID   32453554 – via Nature.
  35. ↑ Gutensohn M, Fan E, Frielingsdorf S, Hanner P, Hou B, Hust B, Klosgen R (2005). "Toc, Tic, Tat et al.: structure and function of protein transport machineries in chloroplasts". Journal of Plant Physiology. 163 (3): 333–347. doi:10.1016/j.jplph.2005.11.009. PMID   16386331 – via PubMed.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ↑ Sharma M, Bennewitz B, Klösgen RB (December 2018). "Rather rule than exception? How to evaluate the relevance of dual protein targeting to mitochondria and chloroplasts". Photosynthesis Research. 138 (3): 335–343. Bibcode:2018PhoRe.138..335S. doi:10.1007/s11120-018-0543-7. PMID   29946965. S2CID   49427254.
  37. 1 2 3 4 5 6 7 8 Alberts B, Johnson A, Lewis J (2002). Molecular Biology of the Cell (4th ed.). New York, NY: Garland Science.{{cite book}}: CS1 maint: multiple names: authors list (link)
  38. ↑ Encyclopedia of biological chemistry. Lennarz, William J.,, Lane, M. Daniel (Second ed.). London. 8 January 2013. ISBN   978-0-12-378631-9. OCLC   828743403.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  39. ↑ Keller G, Gould S, Deluca M, Subramani S (1987). "Firefly luciferase is targeted to peroxisomes in mammalian cells". Proceedings of the National Academy of Sciences. 84 (10): 3264–3268. Bibcode:1987PNAS...84.3264K. doi: 10.1073/pnas.84.10.3264 . PMC   304849 . PMID   3554235.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ↑ Saryi NA, Hutchinson JD, Al-Hejjaj MY, Sedelnikova S, Baker P, Hettema EH (February 2017). "Pnc1 piggy-back import into peroxisomes relies on Gpd1 homodimerisation". Scientific Reports. 7 (1): 42579. Bibcode:2017NatSR...742579S. doi:10.1038/srep42579. PMC   5314374 . PMID   28209961.
  41. 1 2 Baker A, Hogg T, Warriner S (2016). "Peroxisome protein import: a complex journey". Biochemical Society Transactions. 44 (3): 783–789. doi:10.1042/BST20160036. PMC   4900764 . PMID   27284042.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ↑ Gould S, Collins C (2002). "Peroxisomal-protein import: is it really that complex?". Nature Rev. Mol. Cell Biol. 3 (5): 382–389. doi: 10.1038/nrm807 . PMID   11988772. S2CID   2522184.
  43. ↑ MacLeod DA, Rhinn H, Kuwahara T, Zolin A, Di Paolo G, McCabe BD, et al. (February 2013). "RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk". Neuron. 77 (3): 425–39. doi:10.1016/j.neuron.2012.11.033. PMC   3646583 . PMID   23395371.
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