| Structural highlights
Disease
[SQSTM_HUMAN] Defects in SQSTM1 are a cause of Paget disease of bone (PDB) [MIM:602080]. PDB is a metabolic bone disease affecting the axial skeleton and characterized by focal areas of increased and disorganized bone turn-over due to activated osteoclasts. Manifestations of the disease include bone pain, deformity, pathological fractures, deafness, neurological complications and increased risk of osteosarcoma. PDB is a chronic disease affecting 2 to 3% of the population above the age of 40 years.[1] [2] [3] [4] [5] [6] [7] [8] Note=In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinylated protein aggregates.[9]
Function
[SQSTM_HUMAN] Required both for the formation and autophagic degradation of polyubiquitin-containing bodies, called ALIS (aggresome-like induced structures). Links ALIS to the autophagic machinery via direct interaction with MAP1 LC3 family members. May regulate the activation of NFKB1 by TNF-alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The p62 protein (also known as SQSTM1) mediates diverse cellular functions including control of NFkappaB signaling and transcriptional activation. p62 binds non-covalently to ubiquitin and co-localizes with ubiquitylated inclusions in a number of human protein aggregation diseases. Mutations in the gene encoding p62 cause Paget's disease of bone (PDB), a common disorder of the elderly characterized by excessive bone resorption and formation. All of the p62 PDB mutations identified to date cluster within the C-terminal region of the protein, which shows low sequence identity to previously characterized ubiquitin-associated (UBA) domains. We report the first NMR structure of a recombinant polypeptide that contains the C-terminal UBA domain of the human p62 protein (residues 387-436). This sequence, which confers multiubiquitin chain binding, forms a compact three-helix bundle with a structure analogous to the UBA domains of HHR23A but with differences in the loop regions connecting helices that may be involved in binding accessory proteins. We show that the Pro392 --> Leu PDB substitution mutation modifies the structure of the UBA domain by extending the N terminus of helix 1. In contrast to the p62 PDB deletion mutations that remove the UBA domain and ablate multiubiquitin chain binding, the Pro392 --> Leu substitution does not affect interaction of the UBA domain with multiubiquitin chains. Thus, phenotypically identical substitution and deletion mutations do not appear to predispose to PDB through a mechanism dependent on a common loss of ubiquitin chain binding by p62.
Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone.,Ciani B, Layfield R, Cavey JR, Sheppard PW, Searle MS J Biol Chem. 2003 Sep 26;278(39):37409-12. Epub 2003 Jul 11. PMID:12857745[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Long J, Garner TP, Pandya MJ, Craven CJ, Chen P, Shaw B, Williamson MP, Layfield R, Searle MS. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. J Mol Biol. 2010 Feb 12;396(1):178-94. Epub 2009 Nov 17. PMID:19931284 doi:10.1016/j.jmb.2009.11.032
- ↑ Laurin N, Brown JP, Morissette J, Raymond V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet. 2002 Jun;70(6):1582-8. Epub 2002 Apr 30. PMID:11992264 doi:10.1086/340731
- ↑ Hocking LJ, Lucas GJ, Daroszewska A, Mangion J, Olavesen M, Cundy T, Nicholson GC, Ward L, Bennett ST, Wuyts W, Van Hul W, Ralston SH. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum Mol Genet. 2002 Oct 15;11(22):2735-9. PMID:12374763
- ↑ Johnson-Pais TL, Wisdom JH, Weldon KS, Cody JD, Hansen MF, Singer FR, Leach RJ. Three novel mutations in SQSTM1 identified in familial Paget's disease of bone. J Bone Miner Res. 2003 Oct;18(10):1748-53. PMID:14584883
- ↑ Eekhoff EW, Karperien M, Houtsma D, Zwinderman AH, Dragoiescu C, Kneppers AL, Papapoulos SE. Familial Paget's disease in The Netherlands: occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations. Arthritis Rheum. 2004 May;50(5):1650-4. PMID:15146436 doi:10.1002/art.20224
- ↑ Good DA, Busfield F, Fletcher BH, Lovelock PK, Duffy DL, Kesting JB, Andersen J, Shaw JT. Identification of SQSTM1 mutations in familial Paget's disease in Australian pedigrees. Bone. 2004 Jul;35(1):277-82. PMID:15207768 doi:10.1016/j.bone.2004.01.010
- ↑ Falchetti A, Di Stefano M, Marini F, Del Monte F, Mavilia C, Strigoli D, De Feo ML, Isaia G, Masi L, Amedei A, Cioppi F, Ghinoi V, Bongi SM, Di Fede G, Sferrazza C, Rini GB, Melchiorre D, Matucci-Cerinic M, Brandi ML. Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB). J Bone Miner Res. 2004 Jun;19(6):1013-7. Epub 2004 Feb 2. PMID:15125799 doi:10.1359/JBMR.040203
- ↑ Hocking LJ, Lucas GJ, Daroszewska A, Cundy T, Nicholson GC, Donath J, Walsh JP, Finlayson C, Cavey JR, Ciani B, Sheppard PW, Searle MS, Layfield R, Ralston SH. Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences. J Bone Miner Res. 2004 Jul;19(7):1122-7. Epub 2004 Mar 22. PMID:15176995 doi:10.1359/JBMR.040315
- ↑ Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005 Nov 21;171(4):603-14. Epub 2005 Nov 14. PMID:16286508 doi:10.1083/jcb.200507002
- ↑ 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. 1999 Jun 1;18(11):3044-53. PMID:10356400 doi:10.1093/emboj/18.11.3044
- ↑ Sanz L, Diaz-Meco MT, Nakano H, Moscat J. The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway. EMBO J. 2000 Apr 3;19(7):1576-86. PMID:10747026 doi:10.1093/emboj/19.7.1576
- ↑ Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. Epub 2001 Jan 22. PMID:11244088 doi:10.1074/jbc.C000869200
- ↑ Geetha T, Wooten MW. Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling. J Biol Chem. 2003 Feb 14;278(7):4730-9. Epub 2002 Dec 5. PMID:12471037 doi:10.1074/jbc.M208468200
- ↑ Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW. Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol. 2004 Sep;24(18):8055-68. PMID:15340068 doi:10.1128/MCB.24.18.8055-8068.2004
- ↑ Wooten MW, Geetha T, Seibenhener ML, Babu JR, Diaz-Meco MT, Moscat J. The p62 scaffold regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination. J Biol Chem. 2005 Oct 21;280(42):35625-9. Epub 2005 Aug 3. PMID:16079148 doi:C500237200
- ↑ Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol. 2005 Nov 21;171(4):603-14. Epub 2005 Nov 14. PMID:16286508 doi:10.1083/jcb.200507002
- ↑ Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Neurochem. 2005 Jul;94(1):192-203. PMID:15953362 doi:JNC3181
- ↑ Wang Z, Figueiredo-Pereira ME. Inhibition of sequestosome 1/p62 up-regulation prevents aggregation of ubiquitinated proteins induced by prostaglandin J2 without reducing its neurotoxicity. Mol Cell Neurosci. 2005 Jun;29(2):222-31. PMID:15911346 doi:S1044-7431(05)00047-3
- ↑ Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. Epub 2005 Mar 31. PMID:15802564 doi:1110463
- ↑ Long J, Garner TP, Pandya MJ, Craven CJ, Chen P, Shaw B, Williamson MP, Layfield R, Searle MS. Dimerisation of the UBA domain of p62 inhibits ubiquitin binding and regulates NF-kappaB signalling. J Mol Biol. 2010 Feb 12;396(1):178-94. Epub 2009 Nov 17. PMID:19931284 doi:10.1016/j.jmb.2009.11.032
- ↑ Ciani B, Layfield R, Cavey JR, Sheppard PW, Searle MS. Structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget's disease of bone. J Biol Chem. 2003 Sep 26;278(39):37409-12. Epub 2003 Jul 11. PMID:12857745 doi:10.1074/jbc.M307416200
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