| 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
[KPCZ_RAT] Calcium- and diacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukins production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In NF-kappa-B-mediated inflammatory response, can relieve the SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Is necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells.[10] [11] [12] [13] [14] [15] [16] [17] [18] [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.[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29]
Publication Abstract from PubMed
The atypical PKC isoforms (zeta and i) play essential roles in regulating various cellular processes. Both the hetero-interaction between PKCzeta and p62 through their N-terminal PB1 domains and the homo-oligomerization of p62 via its PB1 domain are critical for the activation of NF-kappaB signaling; however, the molecular mechanisms concerning the formation and regulation of these homotypic complexes remain unclear. Here we determined the crystal structure of PKCzeta-PB1 in complex with a monomeric p62-PB1 mutant, where the massive electrostatic interactions between the acidic OPCA motif of PKCzeta-PB1 and the basic surface of p62-PB1, as well as additional hydrogen bonds, ensure the formation of a stable and specific complex. The PKCzeta-p62 interaction is interfered with the modification of a specific Cys of PKCzeta by the antiarthritis drug aurothiomalate, though all four cysteine residues in the PKCzeta-PB1 domain can be modified in in vitro assay. In addition, detailed structural and biochemical analyses demonstrate that the PB1 domains of aPKCs belong to the type I group, which can depolymerize the high-molecular-weight p62 aggregates into homo-oligomers of lower order. These data together unravel the molecular mechanisms of the homo-or hetero-interactions between p62 and PKCzeta and provide the basis for designing inhibitors of NF-kappaB signaling.
Structural and biochemical insights into the homotypic PB1-PB1 complex between PKCzeta and p62.,Ren J, Wang J, Wang Z, Wu J Sci China Life Sci. 2014 Jan;57(1):69-80. doi: 10.1007/s11427-013-4592-z. Epub, 2013 Dec 26. PMID:24369353[30]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Sacktor TC, Osten P, Valsamis H, Jiang X, Naik MU, Sublette E. Persistent activation of the zeta isoform of protein kinase C in the maintenance of long-term potentiation. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8342-6. PMID:8378304
- ↑ Berra E, Diaz-Meco MT, Lozano J, Frutos S, Municio MM, Sanchez P, Sanz L, Moscat J. Evidence for a role of MEK and MAPK during signal transduction by protein kinase C zeta. EMBO J. 1995 Dec 15;14(24):6157-63. PMID:8557035
- ↑ Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat J, Farese RV. Protein kinase C-zeta as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J Biol Chem. 1997 Nov 28;272(48):30075-82. PMID:9374484
- ↑ Puls A, Schmidt S, Grawe F, Stabel S. Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6191-6. PMID:9177193
- ↑ Lallena MJ, Diaz-Meco MT, Bren G, Paya CV, Moscat J. Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol. 1999 Mar;19(3):2180-8. PMID:10022904
- ↑ 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
- ↑ Etienne-Manneville S, Hall A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell. 2001 Aug 24;106(4):489-98. PMID:11525734
- ↑ Diaz-Meco MT, Moscat J. MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Mol Cell Biol. 2001 Feb;21(4):1218-27. PMID:11158308 doi:http://dx.doi.org/10.1128/MCB.21.4.1218-1227.2001
- ↑ Ling DS, Benardo LS, Serrano PA, Blace N, Kelly MT, Crary JF, Sacktor TC. Protein kinase Mzeta is necessary and sufficient for LTP maintenance. Nat Neurosci. 2002 Apr;5(4):295-6. PMID:11914719 doi:http://dx.doi.org/10.1038/nn829
- ↑ 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
- ↑ Ren J, Wang J, Wang Z, Wu J. Structural and biochemical insights into the homotypic PB1-PB1 complex between PKCzeta and p62. Sci China Life Sci. 2014 Jan;57(1):69-80. doi: 10.1007/s11427-013-4592-z. Epub, 2013 Dec 26. PMID:24369353 doi:http://dx.doi.org/10.1007/s11427-013-4592-z
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