Nuclear pore glycoprotein p62 explained

Nuclear pore glycoprotein p62is 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^[1] followed by modification that involve addition of N-acetylglucosamine residues,^[2] followed by association with other complex proteins. In humans it is encoded by the NUP62 gene. 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 nucleus and the cytoplasm. Nucleoporins are the main components of the nuclear pore complex in eukaryotic cells. The protein encoded by this gene is a member of the FG repeat containing nucleoporins and is localized to the nuclear pore central plug. This protein associates with the importin alpha/beta complex which is involved in the import of proteins containing nuclear localization signals. Multiple transcript variants of this gene encode a single protein isoform.^[3]

Structure

P62 is a serine/threonine rich protein of ~520 amino acids, with tetrapeptide repeats on the amino terminus and a series of alpha-helical regions with hydrophobic heptad repeats^[4] forming beta-propeller domain. P62 assembles into a complex containing 3 addition proteins, p60, p54 and p45 ^{[5] [6]} forming the p62 complex of ~235 kDa. O-GlcNAcylation appears to be involved in the assembly and disassembly of p62 into higher order complexes, and a serine/threonine rich linker region between Ser270 to Thr294 appear to be regulatory.^[7] The p62 complex is localized to both the nucleoplasmic and cytoplasmic sides of the pore complex and the relative diameter of p62 complex relative to the nuclear pore complex suggests it interacts in pore gating.^[8]

Function

P62 appears to interact with mRNA during transport out of the nucleus.^[9] P62 also interacts with a nuclear transport factor (NTF2) protein that is involved in trafficking proteins between cytoplasm and nucleus.^[10] Another protein, importin (beta) binds to the helical rod section of p62, which alsobinds NTF2 suggesting the formation of a higher order gating complex.^[11] Karyopherin beta2 (transportin), a riboprotein transporter also interacts with p62.^[12] P62 also interacts with Nup93,^[13] and when Nup98 is depleted p62 fails to assemble with nuclear pore complexes.^[14] Mutant pores could not dock/transport proteins with nuclear localization signals or M9 import signals.

Pathology

Antibodies to p62 complex are involved in one or more autoimmune diseases. P62 glycosylation is increased in diabetes^[15] and may influence its association with other diseases. p62 is also more frequent in Stage IV primary biliary cirrhosis and is prognostic for severe disease.^[16]

Interactions

Nucleoporin 62 has been shown to interact with:

• HSF2,^[17]
• KPNB1,^[18]
• NUTF2,^{[19] [20]}
• TRAF3,^[21] and
• XPO1,^{[22] [23]}
• Nup93.^[13]

Further reading

• Stoffler D, Fahrenkrog B, Aebi U . The nuclear pore complex: from molecular architecture to functional dynamics . Curr. Opin. Cell Biol. . 11 . 3 . 391–401 . 1999 . 10395558 . 10.1016/S0955-0674(99)80055-6 .
• Geetha T, Wooten MW . Structure and functional properties of the ubiquitin binding protein p62 . FEBS Lett. . 512 . 1–3 . 19–24 . 2002 . 11852044 . 10.1016/S0014-5793(02)02286-X . 22029085 . free .
• Carmo-Fonseca M, Kern H, Hurt EC . Human nucleoporin p62 and the essential yeast nuclear pore protein NSP1 show sequence homology and a similar domain organization . Eur. J. Cell Biol. . 55 . 1 . 17–30 . 1991 . 1915414 .
• Paschal BM, Gerace L . Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62 . J. Cell Biol. . 129 . 4 . 925–37 . 1995 . 7744965 . 2120498 . 10.1083/jcb.129.4.925 .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Grote M, Kubitscheck U, Reichelt R, Peters R . Mapping of nucleoporins to the center of the nuclear pore complex by post-embedding immunogold electron microscopy . J. Cell Sci. . 108 . 9 . 2963–72 . 1996 . 10.1242/jcs.108.9.2963 . 8537436 .
• Guan T, Müller S, Klier G, Panté N, Blevitt JM, Haner M, Paschal B, Aebi U, Gerace L . Structural analysis of the p62 complex, an assembly of O-linked glycoproteins that localizes near the central gated channel of the nuclear pore complex . Mol. Biol. Cell . 6 . 11 . 1591–603 . 1996 . 8589458 . 301313 . 10.1091/mbc.6.11.1591 .
• Park I, Chung J, Walsh CT, Yun Y, Strominger JL, Shin J . Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) domain of p56lck and its regulation by phosphorylation of Ser-59 in the lck unique N-terminal region . Proc. Natl. Acad. Sci. U.S.A. . 92 . 26 . 12338–42 . 1996 . 8618896 . 40352 . 10.1073/pnas.92.26.12338 . free .
• Joung I, Strominger JL, Shin J . Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 domain . Proc. Natl. Acad. Sci. U.S.A. . 93 . 12 . 5991–5 . 1996 . 8650207 . 39176 . 10.1073/pnas.93.12.5991 . 1996PNAS...93.5991J . free .
• Vadlamudi RK, Joung I, Strominger JL, Shin J . p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins . J. Biol. Chem. . 271 . 34 . 20235–7 . 1996 . 8702753 . 10.1074/jbc.271.34.20235 . free .
• Hu T, Guan T, Gerace L . Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins . J. Cell Biol. . 134 . 3 . 589–601 . 1996 . 8707840 . 2120945 . 10.1083/jcb.134.3.589 .
• Bullock TL, Clarkson WD, Kent HM, Stewart M . The 1.6 angstroms resolution crystal structure of nuclear transport factor 2 (NTF2) . J. Mol. Biol. . 260 . 3 . 422–31 . 1996 . 8757804 . 10.1006/jmbi.1996.0411 .
• Percipalle P, Clarkson WD, Kent HM, Rhodes D, Stewart M . Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import . J. Mol. Biol. . 266 . 4 . 722–32 . 1997 . 9102465 . 10.1006/jmbi.1996.0801 .
• Yaseen NR, Blobel G . Cloning and characterization of human karyopherin β3 . Proc. Natl. Acad. Sci. U.S.A. . 94 . 9 . 4451–6 . 1997 . 9114010 . 20743 . 10.1073/pnas.94.9.4451 . 1997PNAS...94.4451Y . free .
• Yoshima T, Yura T, Yanagi H . The trimerization domain of human heat shock factor 2 is able to interact with nucleoporin p62 . Biochem. Biophys. Res. Commun. . 240 . 1 . 228–33 . 1997 . 9367915 . 10.1006/bbrc.1997.7662 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Kehlenbach RH, Dickmanns A, Kehlenbach A, Guan T, Gerace L . A Role for RanBP1 in the Release of CRM1 from the Nuclear Pore Complex in a Terminal Step of Nuclear Export . J. Cell Biol. . 145 . 4 . 645–57 . 1999 . 10330396 . 2133185 . 10.1083/jcb.145.4.645 .
• Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J . The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation . EMBO J. . 18 . 11 . 3044–53 . 1999 . 10356400 . 1171386 . 10.1093/emboj/18.11.3044 .
• Rachubinski RA, Marcus SL, Capone JP . The p56(lck)-interacting protein p62 stimulates transcription via the SV40 enhancer . J. Biol. Chem. . 274 . 26 . 18278–84 . 1999 . 10373430 . 10.1074/jbc.274.26.18278 . free .

Notes and References

1. Davis LI, Blobel G . Identification and characterization of a nuclear pore complex protein . Cell . 45 . 5 . 699–709 . 1986 . 3518946 . 10.1016/0092-8674(86)90784-1 . 22170880 .
2. Davis LI, Blobel G . Nuclear pore complex contains a family of glycoproteins that includes p62: glycosylation through a previously unidentified cellular pathway . Proc. Natl. Acad. Sci. U.S.A. . 84 . 21 . 7552–6 . 1987 . 3313397 . 299337 . 10.1073/pnas.84.21.7552 . 1987PNAS...84.7552D . free .
3. Web site: Entrez Gene: NUP62 nucleoporin 62kDa.
4. Starr CM, D'Onofrio M, Park MK, Hanover JA . Primary sequence and heterologous expression of nuclear pore glycoprotein p62 . J. Cell Biol. . 110 . 6 . 1861–71 . 1990 . 2190987 . 2116139 . 10.1083/jcb.110.6.1861 .
5. Kita K, Omata S, Horigome T . Purification and characterization of a nuclear pore glycoprotein complex containing p62 . J. Biochem. . 113 . 3 . 377–82 . 1993 . 8486610 . 10.1093/oxfordjournals.jbchem.a124054.
6. Buss F, Stewart M . Macromolecular interactions in the nucleoporin p62 complex of rat nuclear pores: binding of nucleoporin p54 to the rod domain of p62 . J. Cell Biol. . 128 . 3 . 251–61 . 1995 . 7531196 . 2120351 . 10.1083/jcb.128.3.251 .
7. Lubas WA, Smith M, Starr CM, Hanover JA . Analysis of nuclear pore protein p62 glycosylation . Biochemistry . 34 . 5 . 1686–94 . 1995 . 7849028 . 10.1021/bi00005a025 .
8. Guan T, Müller S, Klier G, Panté N, Blevitt JM, Haner M, Paschal B, Aebi U, Gerace L . Structural analysis of the p62 complex, an assembly of O-linked glycoproteins that localizes near the central gated channel of the nuclear pore complex . Mol. Biol. Cell . 6 . 11 . 1591–603 . 1995 . 8589458 . 301313 . 10.1091/mbc.6.11.1591 .
9. Dargemont C, Schmidt-Zachmann MS, Kühn LC . Direct interaction of nucleoporin p62 with mRNA during its export from the nucleus . J. Cell Sci. . 108 . 1 . 257–63 . 1995 . 10.1242/jcs.108.1.257 . 7738103 . free .
10. Bullock TL, Clarkson WD, Kent HM, Stewart M . The 1.6 angstroms resolution crystal structure of nuclear transport factor 2 (NTF2) . J. Mol. Biol. . 260 . 3 . 422–31 . 1996 . 8757804 . 10.1006/jmbi.1996.0411 .
11. Percipalle P, Clarkson WD, Kent HM, Rhodes D, Stewart M . Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import . J. Mol. Biol. . 266 . 4 . 722–32 . 1997 . 9102465 . 10.1006/jmbi.1996.0801 .
12. Yaseen NR, Blobel G . Cloning and characterization of human karyopherin β3 . Proc. Natl. Acad. Sci. U.S.A. . 94 . 9 . 4451–6 . 1997 . 9114010 . 20743 . 10.1073/pnas.94.9.4451 . 1997PNAS...94.4451Y . free .
13. Grandi P, Dang T, Pané N, Shevchenko A, Mann M, Forbes D, Hurt E . Nup93, a Vertebrate Homologue of Yeast Nic96p, Forms a Complex with a Novel 205-kDa Protein and Is Required for Correct Nuclear Pore Assembly . Mol. Biol. Cell . 8 . 10 . 2017–38 . 1997 . 9348540 . 25664 . 10.1091/mbc.8.10.2017 .
14. Wu X, Kasper LH, Mantcheva RT, Mantchev GT, Springett MJ, van Deursen JM . Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function . Proc. Natl. Acad. Sci. U.S.A. . 98 . 6 . 3191–6 . 2001 . 11248054 . 30629 . 10.1073/pnas.051631598 . 2001PNAS...98.3191W . free .
15. Han I, Oh ES, Kudlow JE . 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 . 2000 . 10926833 . 1221231 . 10.1042/0264-6021:3500109 .
16. 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 . 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 . 2003 . 12753810 . 10.1016/S0896-8411(03)00033-7 .
17. Yoshima T, Yura T, Yanagi H . The trimerization domain of human heat shock factor 2 is able to interact with nucleoporin p62 . Biochem. Biophys. Res. Commun. . 240 . 1 . 228–33 . Nov 1997 . 9367915 . 10.1006/bbrc.1997.7662 .
18. Ben-Efraim I, Gerace L . Gradient of increasing affinity of importin beta for nucleoporins along the pathway of nuclear import . J. Cell Biol. . 152 . 2 . 411–7 . Jan 2001 . 11266456 . 2199621 . 10.1083/jcb.152.2.411.
19. Hu T, Guan T, Gerace L . Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins . J. Cell Biol. . 134 . 3 . 589–601 . Aug 1996 . 8707840 . 2120945 . 10.1083/jcb.134.3.589.
20. Paschal BM, Gerace L . Identification of NTF2, a cytosolic factor for nuclear import that interacts with nuclear pore complex protein p62 . J. Cell Biol. . 129 . 4 . 925–37 . May 1995 . 7744965 . 2120498 . 10.1083/jcb.129.4.925.
21. Gamper C, van Eyndhoven WG, Schweiger E, Mossbacher M, Koo B, Lederman S . TRAF-3 interacts with p62 nucleoporin, a component of the nuclear pore central plug that binds classical NLS-containing import complexes . Mol. Immunol. . 37 . 1–2 . 73–84 . 10781837 . 10.1016/S0161-5890(00)00015-8. 2000.
22. Kehlenbach RH, Dickmanns A, Kehlenbach A, Guan T, Gerace L . A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export . J. Cell Biol. . 145 . 4 . 645–57 . May 1999 . 10330396 . 2133185 . 10.1083/jcb.145.4.645.
23. Lindsay ME, Holaska JM, Welch K, Paschal BM, Macara IG . Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export . J. Cell Biol. . 153 . 7 . 1391–402 . Jun 2001 . 11425870 . 2150735 . 10.1083/jcb.153.7.1391.