Reviewed, UniProtKB/Swiss-Prot Q13501 (SQSTM_HUMAN)

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

Name:	SQSTM1
Synonyms:	ORCA, OSIL

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

Keywords
Biological process	Apoptosis Differentiation Immune response
Cellular component	Cytoplasm Endosome Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Zinc-finger
Ligand	Metal-binding Zinc
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW endosome transport Ref.36 Traceable author statement. Source: UniProtKB immune response Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of transcription from RNA polymerase II promoter Ref.36 Traceable author statement. Source: UniProtKB protein localization Ref.2 Traceable author statement. Source: UniProtKB regulation of I-kappaB kinase/NF-kappaB cascade Ref.36 Inferred from mutant phenotype. Source: UniProtKB response to stress Ref.36 Traceable author statement. Source: UniProtKB ubiquitin-dependent protein catabolic process Ref.7 Traceable author statement. Source: ProtInc
Cellular component	cytosol Ref.2 Traceable author statement. Source: UniProtKB late endosome Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	SH2 domain binding Ref.2 Inferred from direct assay. Source: UniProtKB protein kinase binding Ref.2 Inferred from direct assay. Source: UniProtKB receptor tyrosine kinase binding Ref.2 Traceable author statement. Source: ProtInc ubiquitin binding Ref.36 Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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

1

.

.

.

.

.

.

.

.

440

Helix Strand Turn

Details...

Helix

392 – 402

11

Helix

412 – 419

8

Turn

420 – 422

3

Helix

424 – 431

8

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 462D94C171F337CD	FASTA	440	47,687
	10 20 30 40 50 60 MASLTVKAYL LGKEDAAREI RRFSFCCSPE PEAEAEAAAG PGPCERLLSR VAALFPALRP 70 80 90 100 110 120 GGFQAHYRDE DGDLVAFSSD EELTMAMSYV KDDIFRIYIK EKKECRRDHR PPCAQEAPRN 130 140 150 160 170 180 MVHPNVICDG CNGPVVGTRY KCSVCPDYDL CSVCEGKGLH RGHTKLAFPS PFGHLSEGFS 190 200 210 220 230 240 HSRWLRKVKH GHFGWPGWEM GPPGNWSPRP PRAGEARPGP TAESASGPSE DPSVNFLKNV 250 260 270 280 290 300 GESVAAALSP LGIEVDIDVE HGGKRSRLTP VSPESSSTEE KSSSQPSSCC SDPSKPGGNV 310 320 330 340 350 360 EGATQSLAEQ MRKIALESEG RPEEQMESDN CSGGDDDWTH LSSKEVDPST GELQSLQMPE 370 380 390 400 410 420 SEGPSSLDPS QEGPTGLKEA ALYPHLPPEA DPRLIESLSQ MLSMGFSDEG GWLTRLLQTK 430 440 NYDIGAALDT IQYSKHPPPL
	Isoform 2 [UniParc]. Checksum: 56E985FFBF86EC1B		356	38,629
	10 20 30 40 50 60 MAMSYVKDDI FRIYIKEKKE CRRDHRPPCA QEAPRNMVHP NVICDGCNGP VVGTRYKCSV 70 80 90 100 110 120 CPDYDLCSVC EGKGLHRGHT KLAFPSPFGH LSEGFSHSRW LRKVKHGHFG WPGWEMGPPG 130 140 150 160 170 180 NWSPRPPRAG EARPGPTAES ASGPSEDPSV NFLKNVGESV AAALSPLGIE VDIDVEHGGK 190 200 210 220 230 240 RSRLTPVSPE SSSTEEKSSS QPSSCCSDPS KPGGNVEGAT QSLAEQMRKI ALESEGRPEE 250 260 270 280 290 300 QMESDNCSGG DDDWTHLSSK EVDPSTGELQ SLQMPESEGP SSLDPSQEGP TGLKEAALYP 310 320 330 340 350 HLPPEADPRL IESLSQMLSM GFSDEGGWLT RLLQTKNYDI GAALDTIQYS KHPPPL

References

	« Hide 'large scale' referencesShow '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