SIAH2_RAT
ID SIAH2_RAT Reviewed; 325 AA.
AC Q8R4T2; Q920M8;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 2.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=E3 ubiquitin-protein ligase SIAH2;
DE EC=2.3.2.27 {ECO:0000269|PubMed:11786535};
DE AltName: Full=RING-type E3 ubiquitin transferase SIAH2 {ECO:0000305};
DE AltName: Full=Seven in absentia homolog 2;
DE Short=Siah-2;
GN Name=Siah2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Yamaguchi A., Hori O., Tohyama M.;
RT "Rat Siah1A.";
RL Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 71-325, FUNCTION IN SYP DEGRADATION, AND
RP INTERACTION WITH UBE2E2.
RC STRAIN=Sprague-Dawley;
RX PubMed=11786535; DOI=10.1074/jbc.m107857200;
RA Wheeler T.C., Chin L.-S., Li Y., Roudabush F.L., Li L.;
RT "Regulation of synaptophysin degradation by mammalian homologues of Seven
RT in Absentia.";
RL J. Biol. Chem. 277:10273-10282(2002).
RN [3]
RP INTERACTION WITH SNCAIP.
RX PubMed=15064394; DOI=10.1073/pnas.0401081101;
RA Liani E., Eyal A., Avraham E., Shemer R., Szargel R., Berg D.,
RA Bornemann A., Riess O., Ross C.A., Rott R., Engelender S.;
RT "Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence
RT in cellular inclusions and Lewy bodies imply a role in Parkinson's
RT disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:5500-5505(2004).
RN [4]
RP SUBCELLULAR LOCATION, INTERACTION WITH SNCAIP, AND TISSUE SPECIFICITY.
RX PubMed=19224863; DOI=10.1074/jbc.m805990200;
RA Szargel R., Rott R., Eyal A., Haskin J., Shani V., Balan L., Wolosker H.,
RA Engelender S.;
RT "Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates
RT alpha-synuclein monoubiquitylation and inclusion formation.";
RL J. Biol. Chem. 284:11706-11716(2009).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and
CC subsequent proteasomal degradation of target proteins
CC (PubMed:11786535). E3 ubiquitin ligases accept ubiquitin from an E2
CC ubiquitin-conjugating enzyme in the form of a thioester and then
CC directly transfers the ubiquitin to targeted substrates
CC (PubMed:11786535). Mediates E3 ubiquitin ligase activity either through
CC direct binding to substrates or by functioning as the essential RING
CC domain subunit of larger E3 complexes (By similarity). Mediates
CC ubiquitination and proteasomal degradation of DYRK2 in response to
CC hypoxia (By similarity). Promotes monoubiquitination of SNCA (By
CC similarity). Triggers the ubiquitin-mediated degradation of many
CC substrates, including proteins involved in transcription regulation
CC (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an
CC antiapoptotic protein (BAG1), and a protein involved in synaptic
CC vesicle function in neurons (SYP) (PubMed:11786535). It is thereby
CC involved in apoptosis, tumor suppression, cell cycle, transcription and
CC signaling processes (By similarity). Has some overlapping function with
CC SIAH1 (By similarity). Triggers the ubiquitin-mediated degradation of
CC TRAF2, whereas SIAH1 does not (By similarity). Regulates cellular clock
CC function via ubiquitination of circadian transcriptional repressors
CC NR1D1 and NR1D2 leading to their proteasomal degradation. Plays an
CC important role in mediating the rhythmic degradation/clearance of NR1D1
CC and NR1D2 contributing to their circadian profile of protein abundance
CC (By similarity). Mediates ubiquitination and degradation of EGLN2 and
CC EGLN3 in response to the unfolded protein response (UPR), leading to
CC their degradation and subsequent stabilization of ATF4 (By similarity).
CC Also part of the Wnt signaling pathway in which it mediates the Wnt-
CC induced ubiquitin-mediated proteasomal degradation of AXIN1 (By
CC similarity). {ECO:0000250|UniProtKB:O43255,
CC ECO:0000250|UniProtKB:Q06986, ECO:0000269|PubMed:11786535}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:11786535};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:11786535}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with VAV1, without
CC mediating its ubiquitin-mediated degradation (By similarity). Probable
CC component of some large E3 complex possibly composed of UBE2D1, SIAH2,
CC CACYBP/SIP, SKP1, APC and TBL1X (By similarity). Interacts with UBE2I
CC (By similarity). Interacts with UBE2E2 (PubMed:11786535). Interacts
CC with PEG10, which may inhibit its activity (By similarity). Interacts
CC with PEG3 and EGLN2 (By similarity). Interacts with DYRK2 (By
CC similarity). Interacts with SNCAIP (PubMed:15064394, PubMed:19224863).
CC Interacts with NR1D1 and NR1D2 (By similarity). Interacts with DCC (By
CC similarity). Interacts with AXIN1. {ECO:0000250|UniProtKB:O43255,
CC ECO:0000250|UniProtKB:Q06986, ECO:0000269|PubMed:11786535,
CC ECO:0000269|PubMed:15064394, ECO:0000269|PubMed:19224863}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:19224863}. Nucleus
CC {ECO:0000305|PubMed:19224863}. Note=Predominantly cytoplasmic.
CC Partially nuclear. {ECO:0000250|UniProtKB:O43255}.
CC -!- TISSUE SPECIFICITY: Detected in brain (at protein level).
CC {ECO:0000269|PubMed:19224863}.
CC -!- DOMAIN: The RING-type zinc finger domain is essential for ubiquitin
CC ligase activity.
CC -!- DOMAIN: The SBD domain (substrate-binding domain) mediates the
CC homodimerization and the interaction with substrate proteins. It is
CC related to the TRAF family. {ECO:0000250|UniProtKB:P61092}.
CC -!- PTM: Phosphorylated at Thr-24 and Ser-29 by MAPK14, which mediates the
CC degradation by the proteasome of EGLN3. Phosphorylated at Ser-29 by
CC DYRK2; this increases the ubiquitin ligase activity and promotes
CC degradation of EGLN3 (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the SINA (Seven in absentia) family.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AB067815; BAB70754.1; -; mRNA.
DR EMBL; AF389477; AAL91363.1; -; mRNA.
DR RefSeq; NP_604452.1; NM_134457.1.
DR AlphaFoldDB; Q8R4T2; -.
DR SMR; Q8R4T2; -.
DR BioGRID; 250807; 2.
DR STRING; 10116.ENSRNOP00000018488; -.
DR PaxDb; Q8R4T2; -.
DR Ensembl; ENSRNOT00000018488; ENSRNOP00000018488; ENSRNOG00000013703.
DR GeneID; 140593; -.
DR KEGG; rno:140593; -.
DR UCSC; RGD:620778; rat.
DR CTD; 6478; -.
DR RGD; 620778; Siah2.
DR eggNOG; KOG3002; Eukaryota.
DR GeneTree; ENSGT00940000159812; -.
DR HOGENOM; CLU_028215_0_0_1; -.
DR InParanoid; Q8R4T2; -.
DR OMA; NKPCGKQ; -.
DR OrthoDB; 780610at2759; -.
DR PhylomeDB; Q8R4T2; -.
DR Reactome; R-RNO-373752; Netrin-1 signaling.
DR Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q8R4T2; -.
DR Proteomes; UP000002494; Chromosome 2.
DR Bgee; ENSRNOG00000013703; Expressed in testis and 20 other tissues.
DR Genevisible; Q8R4T2; RN.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005769; C:early endosome; IDA:RGD.
DR GO; GO:0043005; C:neuron projection; IDA:RGD.
DR GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IDA:RGD.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; ISS:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; ISO:RGD.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; ISO:RGD.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IDA:RGD.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 2.
DR InterPro; IPR018121; 7-in-absentia-prot_TRAF-dom.
DR InterPro; IPR004162; SINA-like_animal.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR013010; Znf_SIAH.
DR PANTHER; PTHR45877; PTHR45877; 1.
DR Pfam; PF03145; Sina; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS51081; ZF_SIAH; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Biological rhythms; Cell cycle; Cytoplasm; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..325
FT /note="E3 ubiquitin-protein ligase SIAH2"
FT /id="PRO_0000056170"
FT ZN_FING 81..116
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 134..194
FT /note="SIAH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00455"
FT REGION 1..43
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 131..323
FT /note="SBD"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT COMPBIAS 14..32
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 139
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 146
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 158
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 162
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 169
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 176
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 188
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT BINDING 193
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P61092"
FT MOD_RES 6
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 16
FT /note="Phosphoserine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 24
FT /note="Phosphothreonine; by MAPK14"
FT /evidence="ECO:0000250|UniProtKB:Q06986"
FT MOD_RES 29
FT /note="Phosphoserine; by DYRK2 and MAPK14"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 69
FT /note="Phosphoserine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
FT MOD_RES 120
FT /note="Phosphothreonine; by DYRK2"
FT /evidence="ECO:0000250|UniProtKB:O43255"
SQ SEQUENCE 325 AA; 34700 MW; 0E273AD30959982E CRC64;
MSRPSSTGPS ANKPCSKQPP PPQTPHAPSP AAPPAAATIS AAGPGSSAVP AAAAVISGPG
AGGGAGPVSP QHHELTSLFE CPVCFDYVLP PILQCQAGHL VCNQCRQKLS CCPTCRGALT
PSIRNLAMEK VASAVLFPCK YATTGCSLTL HHTEKPEHED ICEYRPYSCP CPGASCKWQG
SLEAVMSHLM HAHKSITTLQ GEDIVFLATD INLPGAVDWV MMQSCFGHHF MLVLEKQEKY
EGHQQFFAIV LLIGTRKQAE NFAYRLELNG NRRRLTWEAT PRSIHDGVAA AIMNSDCLVF
DTAIAHLFAD NGNLGINVTI STCCQ
