Nucleoporin

Last updated
Nucleoporin 133/155, N terminal
Protein NUP133 PDB 1xks.png
This domain has a 7-blade beta-propeller structure (PDB 1XKS).
Identifiers
SymbolNucleoporin_N
Pfam PF08801
InterPro IPR014908
SCOP2 1XKS / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Nucleoporin 133/155, C terminal (ACE2)
Protein NUP107 PDB 3CQC.png
NUP133 (this domain; right) interacting with NUP107 (PDB 3CQC).
Identifiers
SymbolNucleoporin_C
Pfam PF03177
InterPro IPR007187
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 3I4R
FG repeat
Identifiers
SymbolNucleoporin_FG
Pfam PF13634
Pfam clan CL0647
InterPro IPR025574
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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]

Contents

Structure

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. [4]

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. [4] 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. [4]

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. [4] The cytoplasmic end is less elaborate, with eight filaments projecting into the cytoplasm. They don't seem to have a role in nuclear import. [5]

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. [6] 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. [4] NUP98 was previously thought to be an FG nucleoporin, until it was demonstrated that the "FG" in it have a coiled-coil fold. [4]

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. [7] 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. [8]

Evolution

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. [9]

All living eukaryotes share many important components of the NPC, indicating that a complete complex is present in their common ancestor. [10]

Function

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. [11] These karyopherins interact with nucleoporins that contain repeating sequences of the amino acids phenylalanine (F) and glycine (G) (FG repeats). [12] 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. [13] 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. [14] [15]

Transport mechanism

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]

Pathology

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. [7]

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]

Examples

Each individual nucleoporin is named according to its molecular weight (in kilodaltons). Below are several examples of proteins in the nucleoporin family:

Related Research Articles

<span class="mw-page-title-main">Cell nucleus</span> Eukaryotic membrane-bounded organelle containing DNA

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.

<span class="mw-page-title-main">Nuclear pore complex</span> Openings in nuclear envelope of eukaryotic cells

The nuclear pore complex (NPC), is a large protein complex giving rise to the nuclear pore. Nuclear pores are found in the nuclear envelope that surrounds the cell nucleus in eukaryotic cells. The nuclear envelope is studded by a great number of nuclear pores that give access to various molecules, to and from the nucleoplasm and the cytoplasm. Small molecules can diffuse easily but other larger molecules need to be transported across.

<span class="mw-page-title-main">Nucleoplasm</span> Protoplasm that permeates a cells nucleus

The nucleoplasm, also known as karyoplasm, is the 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 act 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).

<span class="mw-page-title-main">Ran (protein)</span> GTPase functioning in nuclear transport

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.

<span class="mw-page-title-main">Nuclear pore glycoprotein p62</span> Protein-coding gene in the species Homo sapiens

Nuclear pore glycoprotein 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. In humans it is encoded by the NUP62 gene.

<span class="mw-page-title-main">Nuclear envelope</span> Nuclear membrane surrounding the nucleus in eukaryotic cells

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.

<span class="mw-page-title-main">KPNB1</span> Protein-coding gene in the species Homo sapiens

Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.

<span class="mw-page-title-main">NUP98</span> Protein-coding gene in the species Homo sapiens

Nuclear pore complex protein Nup98-Nup96 is a protein that in humans is encoded by the NUP98 gene.

<span class="mw-page-title-main">Transportin 1</span> Protein-coding gene in the species Homo sapiens

Transportin-1 is a protein that in humans is encoded by the TNPO1 gene.

<span class="mw-page-title-main">Nucleoporin 214</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 214 (Nup2014) is a protein that in humans is encoded by the NUP214 gene.

<span class="mw-page-title-main">Nucleoporin 88</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 88 (Nup88) is a protein that in humans is encoded by the NUP88 gene.

<span class="mw-page-title-main">Nucleoporin 54</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 54 (Nup54) is a protein that in humans is encoded by the NUP54 gene.

<span class="mw-page-title-main">Nuclear pore complex protein Nup133</span> Protein-coding gene in the species Homo sapiens

Nuclear pore complex protein Nup133, or Nucleoporin Nup133, is a protein that in humans is encoded by the NUP133 gene.

<span class="mw-page-title-main">POM121</span> Protein-coding gene in the species Homo sapiens

Nuclear envelope pore membrane protein POM 121 is a protein that in humans is encoded by the POM121 gene. Alternatively spliced variants that encode different protein isoforms have been described but the full-length nature of only one has been determined.

<span class="mw-page-title-main">Nucleoporin 43</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 43 (Nup43) is a protein that in humans is encoded by the NUP43 gene.

<span class="mw-page-title-main">Inner nuclear membrane protein</span> Protein embedded in inner membrane of nuclear envelope

Inner nuclear membrane proteins are membrane proteins that are embedded in or associated with the inner membrane of the nuclear envelope. There are about 60 INM proteins, most of which are poorly characterized with respect to structure and function. Among the few well-characterized INM proteins are lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1), lamina-associated polypeptide-2 (LAP2), emerin and MAN1.

References

  1. ↑ Doye V, Hurt E (June 1997). "From nucleoporins to nuclear pore complexes". Current Opinion in Cell Biology. 9 (3): 401–11. doi:10.1016/S0955-0674(97)80014-2. PMID   9159086.
  2. 1 2 Han I, Oh ES, Kudlow JE (August 2000). "Responsiveness of the state of O-linked N-acetylglucosamine modification of nuclear pore protein p62 to the extracellular glucose concentration". The Biochemical Journal. 350 Pt 1 (Pt 1): 109–14. doi:10.1042/0264-6021:3500109. PMC   1221231 . PMID   10926833.
  3. 1 2 3 4 Lodish H (2013). Molecular Cell Biology (Seventh ed.). New York: Worth Publ. ISBN   978-1-4292-3413-9.
  4. 1 2 3 4 5 6 Beck, Martin; Hurt, Ed (21 December 2016). "The nuclear pore complex: understanding its function through structural insight". Nature Reviews Molecular Cell Biology. 18 (2): 73–89. doi:10.1038/nrm.2016.147. PMID   27999437. S2CID   35394962 . Retrieved 10 April 2019.
  5. ↑ Walther, TC; Pickersgill, HS; Cordes, VC; Goldberg, MW; Allen, TD; Mattaj, IW; Fornerod, M (8 July 2002). "The cytoplasmic filaments of the nuclear pore complex are dispensable for selective nuclear protein import". The Journal of Cell Biology. 158 (1): 63–77. doi:10.1083/jcb.200202088. PMC   2173022 . PMID   12105182.
  6. ↑ Denning D, Patel S, Uversky V, Fink A, Rexach M (2003). "Disorder in the nuclear pore complex: The FG repeat regions of nucleoporins are natively unfolded". Proc Natl Acad Sci USA. 100 (5): 2450–5. Bibcode:2003PNAS..100.2450D. doi: 10.1073/pnas.0437902100 . PMC   151361 . PMID   12604785.
  7. 1 2 Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, Shibata M, Onozuka Y, Ueno Y, Hashimoto E, Hayashi N, Shibuya A, Amaki S, Miyakawa H (May 2003). "Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study". Journal of Autoimmunity. 20 (3): 247–54. doi:10.1016/S0896-8411(03)00033-7. PMID   12753810.
  8. ↑ Loïodice I, Alves A, Rabut G, Van Overbeek M, Ellenberg J, Sibarita JB, Doye V (July 2004). "The entire Nup107-160 complex, including three new members, is targeted as one entity to kinetochores in mitosis". Molecular Biology of the Cell. 15 (7): 3333–44. doi:10.1091/mbc.E03-12-0878. PMC   452587 . PMID   15146057.
  9. ↑ Whittle, JR; Schwartz, TU (9 October 2009). "Architectural nucleoporins Nup157/170 and Nup133 are structurally related and descend from a second ancestral element". The Journal of Biological Chemistry. 284 (41): 28442–52. doi: 10.1074/jbc.M109.023580 . PMC   2788893 . PMID   19674973.
  10. ↑ Neumann, N; Lundin, D; Poole, AM (8 October 2010). "Comparative genomic evidence for a complete nuclear pore complex in the last eukaryotic common ancestor". PLOS ONE. 5 (10): e13241. Bibcode:2010PLoSO...513241N. doi: 10.1371/journal.pone.0013241 . PMC   2951903 . PMID   20949036.
  11. ↑ Allen NP, Patel SS, Huang L, Chalkley RJ, Burlingame A, Lutzmann M, Hurt EC, Rexach M (December 2002). "Deciphering networks of protein interactions at the nuclear pore complex". Molecular & Cellular Proteomics. 1 (12): 930–46. doi: 10.1074/mcp.t200012-mcp200 . PMID   12543930.
  12. ↑ Peters R (2006). "Introduction to Nucleocytoplasmic Transport". Xenopus Protocols. Methods in Molecular Biology. Vol. 322. pp. 235–58. doi:10.1007/978-1-59745-000-3_17. ISBN   978-1-58829-362-6. PMID   16739728.
  13. ↑ Marfori M, Mynott A, Ellis JJ, Mehdi AM, Saunders NF, Curmi PM, Forwood JK, Bodén M, Kobe B (September 2011). "Molecular basis for specificity of nuclear import and prediction of nuclear localization". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1813 (9): 1562–77. doi: 10.1016/j.bbamcr.2010.10.013 . PMID   20977914.
  14. ↑ Peyro M, Soheilypour M, Lee BL, Mofrad MR (November 2015). "Evolutionarily Conserved Sequence Features Regulate the Formation of the FG Network at the Center of the Nuclear Pore Complex". Scientific Reports. 5: 15795. Bibcode:2015NatSR...515795P. doi:10.1038/srep15795. PMC   4635341 . PMID   26541386.
  15. ↑ Ando D, Colvin M, Rexach M, Gopinathan A (2013-09-16). "Physical motif clustering within intrinsically disordered nucleoporin sequences reveals universal functional features". PLOS ONE. 8 (9): e73831. Bibcode:2013PLoSO...873831A. doi: 10.1371/journal.pone.0073831 . PMC   3774778 . PMID   24066078.
  16. ↑ Avis JM, Clarke PR (October 1996). "Ran, a GTPase involved in nuclear processes: its regulators and effectors". Journal of Cell Science. 109 ( Pt 10) (10): 2423–7. doi:10.1242/jcs.109.10.2423. PMID   8923203.
  17. ↑ Du Y, Wooten MC, Wooten MW (August 2009). "Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease". Neurobiology of Disease. 35 (2): 302–10. doi:10.1016/j.nbd.2009.05.015. PMC   2718328 . PMID   19481605.
  18. ↑ "Entrez Gene: NUP88 nucleoporin 88kDa"
  19. 1 2 Hirano M, Furiya Y, Asai H, Yasui A, Ueno S (February 2006). "ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome". Proc. Natl. Acad. Sci. U.S.A. 103 (7): 2298–303. Bibcode:2006PNAS..103.2298H. doi: 10.1073/pnas.0505598103 . PMC   1413683 . PMID   16467144.
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