Reviewed,
UniProtKB/Swiss-Prot Q13501 (SQSTM_HUMAN)
Last modified
November 25, 2008.
Version 80.
History...
Clusters with 100%,
90%,
50% identity |
Documents (6) |
Third-party data |
Customize display | text xml rdf/xml gff fasta |
Names and origin
| Protein names | Recommended name: Sequestosome-1 Alternative name(s): Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa Ubiquitin-binding protein p62 EBI3-associated protein of 60 kDa Short name=p60 Short name=EBIAP | ||||
| Gene names |
| ||||
| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 440 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Adapter protein which binds ubiquitin and 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. May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. |
| Subunit structure | Homooligomer or heterooligomer; may form homotypic arrays. Interacts directly with PRKCI and PRKCZ Probable. Forms ternary complexes with PRKCZ and KCNAB2 or PRKCZ and GABBR3. Also interacts with KCNAB1, GABRR1, GABRR2 and GABRR3. Forms an NGF-induced complex with IKBKB, PRKCI and TRAF6 By similarity. Interacts with EBI3, LCK, RASA1, PRKCZ, PRKCI, NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5, TRIM55 and MAPKAPK5. Interacts with the proteasome subunits PSMD4 and PSMC2. Interacts with K63-polyubiquitinated MAPT/TAU. Interacts with IKBKB through PRKCZ and PRKCI. Interacts with NGFR through TRAF6 and bridges that complex to NTRK1. Forms a complex with MAP2K5 and PRKCZ or PRKCI. Component of a ternary complex with PAWR and PRKCZ. Upon TNF-alpha stimulation, interacts with RIPK1 problably bridging IKBKB to the TNF-R1 complex composed of TNF-R1/TNFRSF1A, TRADD and RIPK1. Forms a complex with JUB/Ajuba, PRKCZ and TRAF6. |
| Subcellular location | Cytoplasm. Late endosome. Nucleus. Note= Sarcomere By similarity. In cardiac muscles localizes to the sarcomeric band By similarity. Localizes to late endosomes. May also localize to the nucleus. Accumulates in neurofibrillary tangles and in Lewy bodies of neurons from individuals with Alzheimer and Parkinson disease respectively. Enriched in Rosenthal fibers of pilocytic astrocytoma. In liver cells, accumulates in Mallory bodies associated with alcoholic hepatitis, Wilson disease, indian childhood cirrhosis and in hyaline bodies associated with hepatocellular carcinoma. |
| Tissue specificity | Ubiquitously expressed. |
| Induction | By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at protein level). By Phorbol 12-myristate 13-acetate (PMA). |
| Domain | The UBA domain binds specifically 'Lys-63'-linked polyubiquitin chains of polyubiquitinated substrates. Mediates the interaction with TRIM55. The OPR domain mediates homooligomerization and interactions with PRKCZ, PRKCI, MAP2K5 and NBR1. The ZZ-type zinc finger mediates the interaction with RIPK1. |
| Post-translational modification | Phosphorylated. May be phosphorylated by PRKCZ By similarity. Phosphorylated in vitro by TTN. |
| Involvement in disease | Defects in SQSTM1 are a cause of sporadic and familial 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. |
| Sequence similarities | Contains 1 OPR domain. Contains 1 UBA domain. Contains 1 ZZ-type zinc finger. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| MAP1LC3B | Q9GZQ8 | 1 | EBI-307104,EBI-373144 | |
| RAD23A | P54725 | 1 | EBI-307104,EBI-746453 |
Alternative products
| This entry describes 2 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform 1 (identifier: Q13501-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | ||||||
| Isoform 2 (identifier: Q13501-2) The sequence of this isoform differs from the canonical sequence as follows: 1-84: Missing. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | |||||||||||
Molecule processing | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 440 | 440 | Sequestosome-1 | PRO_0000072176 | ||||||||||||
Regions | ||||||||||||||||
| Domain | 20 – 102 | 83 | OPR | |||||||||||||
| Domain | 389 – 434 | 46 | UBA | |||||||||||||
| Zinc finger | 122 – 167 | 46 | ZZ-type | |||||||||||||
| Region | 1 – 50 | 50 | Interaction with LCK | |||||||||||||
| Region | 43 – 107 | 65 | Interaction with PRKCZ and dimerization By similarity | |||||||||||||
| Region | 50 – 80 | 31 | Interaction with PAWR | |||||||||||||
| Region | 122 – 224 | 103 | Interaction with GABRR3 By similarity | |||||||||||||
| Region | 170 – 220 | 51 | LIM protein-binding (LB) | |||||||||||||
| Region | 269 – 440 | 172 | Interaction with NTRK1 By similarity | |||||||||||||
| Motif | 228 – 233 | 6 | TRAF6-binding | |||||||||||||
| Compositional bias | 272 – 294 | 23 | Ser-rich | |||||||||||||
Amino acid modifications | ||||||||||||||||
| Modified residue | 24 | 1 | Phosphoserine By similarity | |||||||||||||
| Modified residue | 148 | 1 | Phosphotyrosine | |||||||||||||
| Modified residue | 170 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 176 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 207 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 269 | 1 | Phosphothreonine | |||||||||||||
| Modified residue | 272 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 276 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 328 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 332 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 355 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 361 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 365 | 1 | Phosphoserine | |||||||||||||
| Modified residue | 366 | 1 | Phosphoserine | |||||||||||||
Natural variations | ||||||||||||||||
| Alternative sequence | 1 – 84 | 84 | Missing in isoform 2. | VSP_015841 | ||||||||||||
| Natural variant | 117 | 1 | A → V | VAR_023590 | ||||||||||||
| Natural variant | 274 | 1 | E → Q | VAR_023591 | ||||||||||||
| Natural variant | 387 | 1 | P → L in PDB. | VAR_023592 | ||||||||||||
| Natural variant | 392 | 1 | P → L in PDB; no effect on polyubiquitin-binding. | VAR_023593 | ||||||||||||
| Natural variant | 399 | 1 | S → P in PDB. | VAR_023594 | ||||||||||||
| Natural variant | 404 | 1 | M → T in PDB. | VAR_023595 | ||||||||||||
| Natural variant | 404 | 1 | M → V in PDB; loss of polyubiquitin-binding. | VAR_023596 | ||||||||||||
| Natural variant | 411 | 1 | G → S in PDB; no effect on polyubiquitin-binding. | VAR_023597 | ||||||||||||
| Natural variant | 425 | 1 | G → R in PDB; loss of polyubiquitin-binding. | VAR_023598 | ||||||||||||
Experimental info | ||||||||||||||||
| Mutagenesis | 7 | 1 | K → A: Loss of interactions with PRKCZ, PRCKI and NBR1. Loss of dimerization; when associated with A-69 | |||||||||||||
| Mutagenesis | 9 | 1 | Y → F: No effect on interaction with LCK | |||||||||||||
| Mutagenesis | 13 | 1 | K → A: No effect on interaction with PRKCI | |||||||||||||
| Mutagenesis | 21 – 22 | 2 | RR → AA: Loss of interaction with PRKCI. Alters dimerization | |||||||||||||
| Mutagenesis | 67 | 1 | Y → A: No effect on interaction with PRKCZ | |||||||||||||
| Mutagenesis | 69 | 1 | D → A: No effect on interactions with PRKCZ, PRKCI and NBR1. Loss of dimerization; when associated with A-7 | |||||||||||||
| Mutagenesis | 71 | 1 | D → A: No effect on interaction with PRKCI | |||||||||||||
| Mutagenesis | 73 | 1 | D → A: No effect on interactions with PRKCZ and PRKCI | |||||||||||||
| Mutagenesis | 80 | 1 | D → A: No effect on interaction with PRKCI | |||||||||||||
| Mutagenesis | 82 | 1 | E → A: No effect on interaction with PRKCI | |||||||||||||
| Mutagenesis | 398 | 1 | L → V: No effect on polyubiquitin-binding | |||||||||||||
| Mutagenesis | 406 | 1 | F → V: Loss of polyubiquitin-binding | |||||||||||||
| Mutagenesis | 413 | 1 | L → V: No effect on polyubiquitin-binding | |||||||||||||
| Mutagenesis | 417 | 1 | L → V: Loss of polyubiquitin-binding | |||||||||||||
| Mutagenesis | 431 | 1 | I → V: Partial loss of polyubiquitin-binding | |||||||||||||
| Sequence conflict | 321 | 1 | R → A in AAA93299. Ref.1 | |||||||||||||
Secondary structure | ||||||||||||||||
Helix Strand Turn | ||||||||||||||||
| Helix | 392 – 402 | 11 | ||||||||||||||
| Helix | 412 – 419 | 8 | ||||||||||||||
| Turn | 420 – 422 | 3 | ||||||||||||||
| Helix | 424 – 431 | 8 | ||||||||||||||
Sequences
| ||||||||||||||||||||||||
References
| « Hide 'large scale' references | |
| [1] | "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes." Devergne O., Hummel M., Koeppen H., Le Beau M.M., Nathanson E.C., Kieff E., Birkenbach M. J. Virol. 70:1143-1153(1996) [PubMed: 8551575] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 345-361 AND 394-411, INTERACTION WITH EBI3. Tissue: B-cell. |
| [2] | "Molecular cloning of a phosphotyrosine-independent ligand of the p56lck SH2 wdomain." Joung I., Strominger J.L., Shin J. Proc. Natl. Acad. Sci. U.S.A. 93:5991-5995(1996) [PubMed: 8650207] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 51-96; 184-187; 213-217; 239-264 AND 268-281, TISSUE SPECIFICITY, INTERACTION WITH LCK, MUTAGENESIS OF TYR-9. Tissue: Cervix carcinoma. |
| [3] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Pancreas, Placenta, Skin and Uterus. |
| [4] | "Genomic structure and promoter analysis of the p62 gene encoding a non-proteasomal multiubiquitin chain binding protein." Vadlamudi R.K., Shin J. FEBS Lett. 435:138-142(1998) [PubMed: 9762895] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72, INDUCTION. |
| [5] | "Analysis of intracytoplasmic hyaline bodies in a hepatocellular carcinoma. Demonstration of p62 as major constituent." Stumptner C., Heid H., Fuchsbichler A., Hauser H., Mischinger H.-J., Zatloukal K., Denk H. Am. J. Pathol. 154:1701-1710(1999) [PubMed: 10362795] [Abstract] Cited for: PROTEIN SEQUENCE OF 51-60; 166-174 AND 379-388, SUBCELLULAR LOCATION. |
| [6] | "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." Park I., Chung J., Walsh C.T., Yun Y., Strominger J.L., Shin J. Proc. Natl. Acad. Sci. U.S.A. 92:12338-12342(1995) [PubMed: 8618896] [Abstract] Cited for: INTERACTION WITH LCK AND RASA1. |
| [7] | "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins." Vadlamudi R.K., Joung I., Strominger J.L., Shin J. J. Biol. Chem. 271:20235-20237(1996) [PubMed: 8702753] [Abstract] Cited for: INTERACTION WITH UBIQUITIN. |
| [8] | "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor." Marcus S.L., Winrow C.J., Capone J.P., Rachubinski R.A. J. Biol. Chem. 271:27197-27200(1996) [PubMed: 8910285] [Abstract] Cited for: INTERACTION WITH NR2F2. |
| [9] | "Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62." Sanchez P., De Carcer G., Sandoval I.V., Moscat J., Diaz-Meco M.T. Mol. Cell. Biol. 18:3069-3080(1998) [PubMed: 9566925] [Abstract] Cited for: INTERACTION WITH PRKCI AND PRKCZ, SUBCELLULAR LOCATION. |
| [10] | "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation." Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J. EMBO J. 18:3044-3053(1999) [PubMed: 10356400] [Abstract] Cited for: INTERACTION WITH RIPK1; PRKCZ; PRKCI; IKBKB; TRADD AND TNFRSF1A, FUNCTION. |
| [11] | "p62 functions as a p38 MAP kinase regulator." Sudo T., Maruyama M., Osada H. Biochem. Biophys. Res. Commun. 269:521-525(2000) [PubMed: 10708586] [Abstract] Cited for: INTERACTION WITH MAPKAPK5, SUBCELLULAR LOCATION. |
| [12] | "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway." Sanz L., Diaz-Meco M.T., Nakano H., Moscat J. EMBO J. 19:1576-1586(2000) [PubMed: 10747026] [Abstract] Cited for: INTERACTION WITH TRAF6 AND RIPK1, DOMAIN, FUNCTION. |
| [13] | "The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor." Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., Barker P.A., Moscat J. J. Biol. Chem. 276:7709-7712(2001) [PubMed: 11244088] [Abstract] Cited for: INTERACTION WITH NTRK1; TRAF6; NGFR AND PRKCZ, FUNCTION. |
| [14] | "p62 Is a common component of cytoplasmic inclusions in protein aggregation diseases." Zatloukal K., Stumptner C., Fuchsbichler A., Heid H., Schnoelzer M., Kenner L., Kleinert R., Prinz M., Aguzzi A., Denk H. Am. J. Pathol. 160:255-263(2002) [PubMed: 11786419] [Abstract] Cited for: SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY. |
| [15] | "p62 forms a ternary complex with PKCzeta and PAR-4 and antagonizes PAR-4-induced PKCzeta inhibition." Chang S., Kim J.H., Shin J. FEBS Lett. 510:57-61(2002) [PubMed: 11755531] [Abstract] Cited for: INTERACTION WITH PAWR AND PRKCZ. |
| [16] | "Mallory body -- a disease-associated type of sequestosome." Stumptner C., Fuchsbichler A., Heid H., Zatloukal K., Denk H. Hepatology 35:1053-1062(2002) [PubMed: 11981755] [Abstract] Cited for: SUBCELLULAR LOCATION. |
| [17] | "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling." Geetha T., Wooten M.W. J. Biol. Chem. 278:4730-4739(2003) [PubMed: 12471037] [Abstract] Cited for: INTERACTION WITH NTRK1; NTRK2 AND NTRK3, SUBCELLULAR LOCATION, FUNCTION. |
| [18] | "Interaction codes within the family of mammalian Phox and Bem1p domain-containing proteins." Lamark T., Perander M., Outzen H., Kristiansen K., Oevervatn A., Michaelsen E., Bjoerkoey G., Johansen T. J. Biol. Chem. 278:34568-34581(2003) [PubMed: 12813044] [Abstract] Cited for: INTERACTION WITH PRKCI; PRKCZ; MAP2K5 AND NBR1, DOMAIN, MUTAGENESIS OF LYS-7; LYS-13; 21-ARG-ARG-22; TYR-67; ASP-69; ASP-71; ASP-73; ASP-80 AND GLU-82, DIMERIZATION. |
| [19] | "PB1 domain-mediated heterodimerization in NADPH oxidase and signaling complexes of atypical protein kinase C with Par6 and p62." Wilson M.I., Gill D.J., Perisic |

Clusters with