Nucleoporin

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Nucleoporin
Identifiers
Symbol Nucleoporin
Pfam PF03177
InterPro IPR004870

The 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 that extends across the nuclear envelope, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores in turn allow the transport of water-soluble 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]

Function[edit]

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, also known as Kaps[4] These karyopherins interact with nucleoporins that contain FG peptide repeats, that is, they contain repeating sequences of the amino acids phenylalanine (F) and glycine (G).[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 a single side of the nuclear pore complex, either cytosolic or nucleoplasmic. Other nucleoporins may be found on both faces.

Structure[edit]

All nucleoporins share some basic structural components. Like all proteins, nucleoporins are composed of strings of amino acids which are linked together by peptide bonds. Each nucleoporin consists of an N-terminus with a free amine group, a C-terminus with a free carboxyl group, and a central binding region. Nucleoporins aggregate to form a nuclear pore complex, an octagonal ring that traverses the nuclear envelope. There are three distinct types of nucleoporins that each have a unique structure and function. These three types are structural nucleoporins, membrane nucleoporins, and FG-nucleoporins.[3]

Structural nucleoporins form the ring portion of the NPC. They span the membrane of the nuclear envelope and are often referred to as the scaffolding of a nuclear pore. Structural nucleoporins come together to form Y-complexes that are composed of seven nucleoporins. Each nuclear pore contains sixteen Y-complexes for a total of 112 structural nucleoporins. The structure of a Y-complex is highly similar to that of COPII. 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]

Membrane nucleoporins are localized to the curvature of a nuclear pore. These proteins are embedded within the nuclear membrane at the region where the inner and outer leaflets connect.

FG-nucleoporins are so named because they contain repeats of the amino acid residues phenylalanine and glycine. FG-repeats are small hydrophobic segments that break up long stretches of hydrophilic amino acids. These FG-repeat segments are found in long random-coil portions of the protein which stretch into the channel of nuclear pores and are primarily responsible for the selective exclusivity of nuclear pore complexes. These segments of FG-nucleoporins 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]

Nucleoporins have been shown to form various subcomplexes with one another. The most common of these complexes is the p62 complex, which is an assembly composed of NUP62, NUP58, NUP54 and NUP45.[7] Another example of such a complex is the NUP107-160 complex, composed of many different nucleoporins. The NUP107-160 complex has been localized to kinetochores and plays a role in mitosis.[8]

Transport Mechanism[edit]

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.[9]

Pathology[edit]

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.[10]

Increased expression of the NUP88 gene, which encodes for nucleoporin 88, is commonly found in precancerous dysplasias and malignant neoplasms.[11]

Examples[edit]

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

References[edit]

  1. ^ Doye V, Hurt E (June 1997). "From nucleoporins to nuclear pore complexes". Curr. Opin. Cell Biol. 9 (3): 401–11. doi:10.1016/S0955-0674(97)80014-2. PMID 9159086. 
  2. ^ a b Han I, Oh ES, Kudlow JE (2000). "Responsiveness of the state of O-linked N-acetylglucosamine modification of nuclear pore protein p62 to the extracellular glucose concentration". Biochem. J. 350 Pt 1 (Pt 1): 109–14. doi:10.1042/0264-6021:3500109. PMC 1221231. PMID 10926833.
  3. ^ a b c d e Lodish H (2013). Molecular Cell Biology (Seventh ed.). New York: Worth Publ. ISBN 1-4292-3413-X. 
  4. ^ Allen NP, Patel SS, Huang L, Chalkley RJ, Burlingame A, Lutzmann M, Hurt EC, Rexach M (2002). "Deciphering networks of protein interactions at the nuclear pore complex". Mol. Cell Proteomics 1 (12): 930–46. doi:10.1074/mcp.t200012-mcp200. PMID 12543930. 
  5. ^ Peters R (2006). "Introduction to nucleocytoplasmic transport: molecules and mechanisms". Methods Mol. Biol. 322: 235–58. doi:10.1007/978-1-59745-000-3_17. PMID 16739728. 
  6. ^ Marfori M, Mynott A, Ellis JJ, Mehdi AM, Saunders NF, Curmi PM, Forwood JK, Bodén M, Kobe B (2011). "Molecular basis for specificity of nuclear import and prediction of nuclear localization". Biochim. Biophys. Acta 1813 (9): 1562–77. doi:10.1016/j.bbamcr.2010.10.013. PMID 20977914. 
  7. ^ a b 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 (2003). "Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study". J. Autoimmun. 20 (3): 247–54. doi:10.1016/S0896-8411(03)00033-7. PMID 12753810.
  8. ^ Loïodice I, Alves A, Rabut G, et al. The Entire Nup107-160 Complex, Including Three New Members, Is Targeted as One Entity to Kinetochores in Mitosis. Silver P, ed. Molecular Biology of the Cell 2004;15(7):3333-3344. doi:10.1091/mbc.E03-12-0878.
  9. ^ Avis JM, Clarke PR (1996). "Ran, a GTPase involved in nuclear processes: its regulators and effectors". J. Cell. Sci. 109 ( Pt 10): 2423–7. PMID 8923203. 
  10. ^ 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. PMID 19481605.
  11. ^ "Entrez Gene: NUP88 nucleoporin 88kDa"

External links[edit]