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E3 ubiquitin-protein ligase SIAH1; seven in absentia homolog 1; siah-1; siah-1a (SIAH1 HUMSIAH)

Function: - E3-ubiquitin ligage that mediates mediates ubiquitination & subsequent proteasomal degradation of target proteins - triggers ubiquitin-mediated degradation of a) proteins involved in transcription regulation (MYB, POU2AF1, PML & RBBP8) b) cell surface receptor (DCC) c) cytoplasmic signal transduction molecules (KLF10/TIEG1 & NUMB) d) an antiapoptotic protein (BAG1) e) microtubule motor protein (KIF22) f) protein involved in synaptic vesicle function in neurons (SYP) f) structural protein (CTNNB1) g) SNCAIP - involved in many cellular processes such as a) apoptosis b) tumor suppression c) cell cycle d) axon guidance e) transcription regulation f) spermatogenesis g) TNF-alpha signaling - has some overlapping function with SIAH2 - induces apoptosis in cooperation with PEG3 - upon nitric oxid (NO) generation that follows apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating translocation of GAPDH to the nucleus - GAPDH acts as a stabilizer of SIAH1, facilitating degradation of nuclear proteins - turnover in the absence of stabilization is rapid - overexpression inhibits cell proliferation, promotes apoptosis & suppresses tumor formation - inhibited by interaction with SNCAIP (isoform 2, but not isoform 1) - may be inhibited by interaction with PEG10 - protein modification; protein ubiquitination - homodimer - interacts with group 1 glutamate receptors GRM1 & GRM5 - interacts with DAB1, which may inhibit its activity - interacts with UBE2E2. interacts with PEG3 - interacts with GAPDH; leading to stabilize SIAH1 (putative) - component of some large E3 complex composed of UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC & TBL1X - interacts with UBE2I - interacts with alpha- tubulin - interacts with PEG10, which may inhibit its activity - interacts with KHDRBS3 - interacts with SNCAIP Structure: - the RING-type Zn+2 finger domain is essential for ubiquitin ligase activity - the SBD domain (substrate-binding domain) mediates homodimerization & interaction with substrates - related to the TRAF family (putative) - belongs to the SINA (seven in absentia) family - contains 1 RING-type Zn+2 finger - contains 1 SIAH-type Zn+2 finger Compartment: - cytoplasm, nucleus - predominantly cytoplasmic, partially nuclear Alternative splicing: named isoforms=3 Expression: - widely expressed at low level - down-regulated in advanced hepatocellular carcinomas - can be induced by p53 & genotoxic stress

Interactions

molecular events

Related

glyceraldehyde-3-phosphate dehydrogenase (GAPDH, GAPD, CDABP0047, OK/SW-cl12) paternally expressed gene 3 protein (PEG3, KIAA0287)

General

E3 ubiquitin ligase; ubiquitin-ligating enzyme E3; N end-recognizing protein zinc finger protein

Properties

SIZE: entity length = 282 aa MW = 31 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: RING-finger {41-76} EFFECTOR-BOUND: Zn+2 FOR-BINDING-OF: DNA motif SBD {90-282} MOTIF: Zinc finger NAME: Zinc finger SITE: 93-153 EFFECTOR-BOUND: Zn+2 Zn+2-binding site SITE: 98-98 Zn+2-binding site SITE: 105-105 Zn+2-binding site SITE: 117-117 Zn+2-binding site SITE: 121-121 Zn+2-binding site SITE: 128-128 Zn+2-binding site SITE: 135-135 Zn+2-binding site SITE: 147-147 Zn+2-binding site SITE: 152-152

Database Correlations

OMIM 602212 UniProt Q8IUQ4 Pfam PF03145 Entrez Gene 6477 Kegg hsa:6477

References

  1. UniProt :accession Q8IUQ4
  2. Relaix F et al. Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2105-10. PMID: 10681424

Component-of

molecular complex