Nucleoporin 133/155, N terminal | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | Nucleoporin_N | ||||||||
Pfam | PF08801 | ||||||||
InterPro | IPR014908 | ||||||||
SCOP2 | 1XKS / SCOPe / SUPFAM | ||||||||
|
Nucleoporin 133/155, C terminal (ACE2) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||||
Symbol | Nucleoporin_C | ||||||||||
Pfam | PF03177 | ||||||||||
InterPro | IPR007187 | ||||||||||
|
FG repeat | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | Nucleoporin_FG | ||||||||
Pfam | PF13634 | ||||||||
Pfam clan | CL0647 | ||||||||
InterPro | IPR025574 | ||||||||
|
Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). [1] The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membranes fuse, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores enable the passive and facilitated transport of molecules across the nuclear envelope. Nucleoporins, a family of around 30 proteins, are the main components of the nuclear pore complex in eukaryotic cells. Nucleoporin 62 is the most abundant member of this family. [2] Nucleoporins are able to transport molecules across the nuclear envelope at a very high rate. A single NPC is able to transport 60,000 protein molecules across the nuclear envelope every minute. [3]
Nucleoporins mediate transport of macromolecules between the cell nucleus and cytoplasm in eukaryotes. Certain members of the nucleoporin family form the structural scaffolding of the nuclear pore complex. However, nucleoporins primarily function by interacting with transport molecules known as karyopherins. [4] These karyopherins interact with nucleoporins that contain repeating sequences of the amino acids phenylalanine (F) and glycine (G) (FG repeats). [5] In doing so, karyopherins are able to shuttle their cargo across the nuclear envelope. Nucleoporins are only required for the transport of large hydrophilic molecules above 40 kDa, as smaller molecules pass through nuclear pores via passive diffusion. Nucleoporins play an important role in the transport of mRNA from the nucleus to the cytoplasm after transcription. [6] Depending on their function, certain nucleoporins are localized to either the cytosolic or nucleoplasmic side of the nuclear pore complex. Other nucleoporins may be found on both sides. It has been recently shown that FG nucleoporins have specific evolutionary conserved features encoded in their sequences that provide insight into how they regulate the transport of molecules through the nuclear pore complex. [7] [8]
Nucleoporins aggregate to form a nuclear pore complex, an octagonal ring that traverses the nuclear envelope. The ring consists of eight scaffold sub-complexes, with two structural layers of COPII-like coating sandwiching some proteins that line the pore. From the cytoplasm to the nucleoplasm, the three layers of the ring complex is named the cytoplasm, inner pore, and nucleoplasm rings respectively. Different sets of proteins associate on either ring, and some transmembrane proteins anchor the assembly to the lipid bilayer. [9]
In a scaffold subcomplex, both the cytoplasm and the nucleoplasm rings are made up of Y-complexes, a protein complex built out of, among others, NUP133 and NUP107. On each end of each of the eight scaffolds are two Y-complexes, adding up to 32 complexes per pore. [9] The relationship of the membrane curvature of a nuclear pore with Y-complexes can be seen as analogous to the budding formation of a COPII coated vesicle. [3] The proteins lining the inner pore make up the NUP62 complex. [9]
On the nucleoplasm side, extra proteins associated with the ring form "the nuclear basket", a complex capable of tethering the nucleoporin to the nuclear lamina and even to specific parts of the genome. [9] The cytoplasmic end is less elaborate, with eight filaments projecting into the cytoplasm. They don't seem to have a role in nuclear import. [10]
Some nucleoporins contain FG repeats. Named after phenylalanine and glycine, FG repeats are small hydrophobic segments that break up long stretches of hydrophilic amino acids. These flexible parts form unfolded, or disordered segments without a fixed structure. [11] They form a mass of chains which allow smaller molecules to diffuse through, but exclude large hydrophilic macromolecules. These large molecules are only able to cross a nuclear pore if they are accompanied by a signaling molecule that temporarily interacts with a nucleoporin's FG repeat segment. FG nucleoporins also contain a globular portion that serves as an anchor for attachment to the nuclear pore complex. [3]
Membrane nucleoporins associate with both the scaffold and the nuclear membrane. Some of them, like GP210, cross the entire membrane, others (like NUP98) act like nails with structural parts for the lining as well as parts that punch into the membrane. [9] NUP98 was previously thought to be an FG nucleoporin, until it was demonstrated that the "FG" in it have a coiled-coil fold. [9]
Nucleoporins have been shown to form various subcomplexes with one another. The most common of these complexes is the nup62 complex, which is an assembly composed of NUP62, NUP58, NUP54 and NUP45. [12] Another example of such a complex is the Y (NUP107-160) complex, composed of many different nucleoporins. The NUP107-160 complex has been localized to kinetochores and plays a role in mitosis. [13]
Many structural nucleoporins contain solenoid protein domains, domains consisting of repeats that can be stacked together as bulk building blocks. There are beta-propeller domain with similarities to WD40 repeats, and more interestingly, unique types of alpha solenoid (bundles of helixes) repeats that form a class of their own, the ancestral coatomer elements (ACE). To date, two classes of ACEs have been identified. ACE1 is a 28-helix domain found in many scaffolding nucleoproteins as well as SEC31, a component of COPII. ACE2, shown in the infobox, is found in yeast Nup157/Nup170 (human Nup155) and Nup133. In either case, the shared domains, like their names suggest, indicate a shared ancestry both within nucleoproteins and between nucleoproteins and cotamers. [14]
All living eukaryotes share many important components of the NPC, indicating that a complete complex is present in their common ancestor. [15]
Nucleoporins regulate the transport of macromolecules through the nuclear envelope via interactions with the transporter molecules karyopherins. Karyopherins will bind to their cargo, and reversibly interact with the FG repeats in nucleoporins. Karyopherins and their cargo are passed between FG repeats until they diffuse down their concentration gradient and through the nuclear pore complex. Karyopherins can serve as an importin (transporting proteins into the nucleus) or an exportin (transporting proteins out of the nucleus). [3] Karyopherins release of their cargo is driven by Ran, a G protein. Ran is small enough that it can diffuse through nuclear pores down its concentration gradient without interacting with nucleoporins. Ran will bind to either GTP or GDP and has the ability to change a karyopherin's affinity for its cargo. Inside the nucleus, RanGTP causes an importin karyopherin to change conformation, allowing its cargo to be released. RanGTP can also bind to exportin karyopherins and pass through the nuclear pore. Once it has reached the cytosol, RanGTP can be hydrolyzed to RanGDP, allowing the exportin's cargo to be released. [16]
Several diseases have been linked to pathologies of nucleoporins, notably diabetes, primary biliary cirrhosis, Parkinson's disease and Alzheimer's disease. Overexpression of the genes that encode for different nucleoporins also have been shown to be related to the formation of cancerous tumors.
Nucleoporins have been shown to be highly sensitive to glucose concentration changes. Therefore, individuals affected by diabetes often exhibit increased glycosylation of nucleoporins, particularly nucleoporin 62. [2]
Autoimmune conditions such as anti-p62 antibodies, which inhibit p62 complexes have links to primary biliary cirrhosis which destroys the bile ducts of the liver. [12]
Decreases in the production of the p62 complex are common to many neurodegenerative diseases. Modification of the p62 promoter by oxidation is correlated with Alzheimer's disease, Huntington's disease, and Parkinson's disease among other neurodegenerative disorders. [17]
Increased expression of the NUP88 gene, which encodes for nucleoporin 88, is commonly found in precancerous dysplasias and malignant neoplasms. [18]
Nucleoporin protein aladin is a component of the nuclear pore complex. Mutations in the aladin gene are responsible for triple-A syndrome, an autosomal recessive neuroendocrinological disease. Mutant aladin causes selective failure of nuclear protein import and hypersensitivity to oxidative stress. [19] The import of DNA repair proteins aprataxin and DNA ligase I is selectively decreased, and this may increase the vulnerability of the cell's DNA to oxidative stress induced damages that trigger cell death. [19]
Each individual nucleoporin is named according to its molecular weight (in kilo Daltons). Below are several examples of proteins in the nucleoporin family:
The cell nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support.
A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexes (NPCs) in the nuclear envelope of a vertebrate cell, but this number varies depending on cell type and the stage in the life cycle. The human nuclear pore complex (hNPC) is a 110 megadalton (MDa) structure. The proteins that make up the nuclear pore complex are known as nucleoporins; each NPC contains at least 456 individual protein molecules and is composed of 34 distinct nucleoporin proteins. About half of the nucleoporins typically contain solenoid protein domains—either an alpha solenoid or a beta-propeller fold, or in some cases both as separate structural domains. The other half show structural characteristics typical of "natively unfolded" or intrinsically disordered proteins, i.e. they are highly flexible proteins that lack ordered tertiary structure. These disordered proteins are the FG nucleoporins, so called because their amino-acid sequence contains many phenylalanine–glycine repeats.
The nucleoplasm is a type of protoplasm that makes up the cell nucleus, the most prominent organelle of the eukaryotic cell. It is enclosed by the nuclear envelope, also known as the nuclear membrane. The nucleoplasm resembles the cytoplasm of a eukaryotic cell in that it is a gel-like substance found within a membrane, although the nucleoplasm only fills out the space in the nucleus and has its own unique functions. The nucleoplasm suspends structures within the nucleus that are not membrane-bound and is responsible for maintaining the shape of the nucleus. The structures suspended in the nucleoplasm include chromosomes, various proteins, nuclear bodies, the nucleolus, nucleoporins, nucleotides, and nuclear speckles.
A nuclear localization signalorsequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different nuclear localized proteins may share the same NLS. An NLS has the opposite function of a nuclear export signal (NES), which targets proteins out of the nucleus.
Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm. Generally, karyopherin-mediated transport occurs through nuclear pores which acts as a gateway into and out of the nucleus. Most proteins require karyopherins to traverse the nuclear pore.
Importin is a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).
Ran also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.
Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association with transport factors known as nuclear transport receptors, like karyopherins called importins to enter the nucleus and exportins to exit.
Nuclear pore glycoprotein-210 (gp210) is an essential trafficking regulator in the eukaryotic nuclear pore complex. Gp-210 anchors the pore complex to the nuclear membrane. and protein tagging reveals its primarily located on the luminal side of double layer membrane at the pore. A single polypeptide motif of gp210 is responsible for sorting to nuclear membrane, and indicate the carboxyl tail of the protein is oriented toward the cytoplasmic side of the membrane.
Nucleoporin p62 (p62) is a protein complex associated with the nuclear envelope. The p62 protein remains associated with the nuclear pore complex-lamina fraction. p62 is synthesized as a soluble cytoplasmic precursor of 61 kDa followed by modification that involve addition of N-acetylglucosamine residues, followed by association with other complex proteins.
The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material.
Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.
Nuclear pore complex protein Nup98-Nup96 is a protein that in humans is encoded by the NUP98 gene.
Nucleoporin 153 (Nup153) is a protein which in humans is encoded by the NUP153 gene. It is an essential component of the basket of nuclear pore complexes (NPCs) in vertebrates, and required for the anchoring of NPCs. It also acts as the docking site of an importing karyopherin. On the cytoplasmic side of the NPC, Nup358 fulfills an analogous role.
Nucleoporin 214 (Nup2014) is a protein that in humans is encoded by the NUP214 gene.
Nucleoporin 88 (Nup88) is a protein that in humans is encoded by the NUP88 gene.
Nucleoporin 50 (Nup50) is a protein that in humans is encoded by the NUP50 gene.
Nucleoporin 54 (Nup54) is a protein that in humans is encoded by the NUP54 gene.
Nucleoporin 37 (Nup37) is a protein that in humans is encoded by the NUP37 gene.
Gene gating is a phenomenon by which transcriptionally active genes are brought next to nuclear pore complexes (NPCs) so that nascent transcripts can quickly form mature mRNA associated with export factors. Gene gating was first hypothesised by Günter Blobel in 1985. It has been shown to occur in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster as well as mammalian model systems.