SIA1A_MOUSE
ID SIA1A_MOUSE Reviewed; 282 AA.
AC P61092; Q06984;
DT 26-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 26-APR-2004, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=E3 ubiquitin-protein ligase SIAH1A;
DE EC=2.3.2.27 {ECO:0000269|PubMed:28546513};
DE AltName: Full=RING-type E3 ubiquitin transferase SIAH1A {ECO:0000305};
DE AltName: Full=Seven in absentia homolog 1a;
DE Short=Siah-1a;
DE Short=Siah1a;
DE Short=mSiah-1a;
GN Name=Siah1a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=SWR/J; TISSUE=Eye;
RX PubMed=8404535; DOI=10.1242/dev.117.4.1333;
RA Della N.G., Senior P.V., Bowtell D.D.L.;
RT "Isolation and characterisation of murine homologues of the Drosophila
RT seven in absentia gene (sina).";
RL Development 117:1333-1343(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Olfactory epithelium;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND INTERACTION WITH PEG3.
RX PubMed=10681424; DOI=10.1073/pnas.040378897;
RA Relaix F., Wei X., Li W., Pan J., Lin Y., Bowtell D.D., Sassoon D.A.,
RA Wu X.;
RT "Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in
RT p53-mediated apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:2105-2110(2000).
RN [4]
RP INTERACTION WITH DAB1.
RX PubMed=12646221; DOI=10.1016/s0006-291x(03)00247-x;
RA Park T.-J., Hamanaka H., Ohshima T., Watanabe N., Mikoshiba K., Nukina N.;
RT "Inhibition of ubiquitin ligase Siah-1A by disabled-1.";
RL Biochem. Biophys. Res. Commun. 302:671-678(2003).
RN [5]
RP FUNCTION.
RX PubMed=11884614; DOI=10.1128/mcb.22.7.2294-2303.2002;
RA Dickins R.A., Frew I.J., House C.M., O'Bryan M.K., Holloway A.J., Haviv I.,
RA Traficante N., de Kretser D.M., Bowtell D.D.L.;
RT "The ubiquitin ligase component Siah1a is required for completion of
RT meiosis I in male mice.";
RL Mol. Cell. Biol. 22:2294-2303(2002).
RN [6]
RP INDUCTION.
RX PubMed=12417719; DOI=10.1128/mcb.22.23.8155-8164.2002;
RA Frew I.J., Dickins R.A., Cuddihy A.R., Del Rosario M., Reinhard C.,
RA O'Connell M.J., Bowtell D.D.L.;
RT "Normal p53 function in primary cells deficient for Siah genes.";
RL Mol. Cell. Biol. 22:8155-8164(2002).
RN [7]
RP FUNCTION, AND INDUCTION.
RX PubMed=24809345; DOI=10.1371/journal.pgen.1004348;
RA Scortegagna M., Kim H., Li J.L., Yao H., Brill L.M., Han J., Lau E.,
RA Bowtell D., Haddad G., Kaufman R.J., Ronai Z.A.;
RT "Fine tuning of the UPR by the ubiquitin ligases Siah1/2.";
RL PLoS Genet. 10:e1004348-e1004348(2014).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND MUTAGENESIS OF 176-VAL--TRP-178.
RX PubMed=28546513; DOI=10.1101/gad.300053.117;
RA Ji L., Jiang B., Jiang X., Charlat O., Chen A., Mickanin C., Bauer A.,
RA Xu W., Yan X., Cong F.;
RT "The SIAH E3 ubiquitin ligases promote Wnt/beta-catenin signaling through
RT mediating Wnt-induced Axin degradation.";
RL Genes Dev. 31:904-915(2017).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 93-282 IN COMPLEX WITH ZINC,
RP HOMODIMERIZATION, AND DOMAIN.
RX PubMed=11742346; DOI=10.1038/nsb743;
RA Polekhina G., House C.M., Traficante N., Mackay J.P., Relaix F.,
RA Sassoon D.A., Parker M.W., Bowtell D.D.L.;
RT "Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-
RT alpha signaling.";
RL Nat. Struct. Biol. 9:68-75(2002).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) OF 92-282 IN COMPLEX WITH ZINC AND
RP PEPTIDE SUBSTRATE, FUNCTION, INTERACTION WITH KLF10, AND MUTAGENESIS OF
RP THR-156; LEU-158; LEU-166 AND MET-180.
RX PubMed=16615911; DOI=10.1016/j.str.2005.12.013;
RA House C.M., Hancock N.C., Moller A., Cromer B.A., Fedorov V., Bowtell D.D.,
RA Parker M.W., Polekhina G.;
RT "Elucidation of the substrate binding site of Siah ubiquitin ligase.";
RL Structure 14:695-701(2006).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination and
CC subsequent proteasomal degradation of target proteins. E3 ubiquitin
CC ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the
CC form of a thioester and then directly transfers the ubiquitin to
CC targeted substrates. Mediates E3 ubiquitin ligase activity either
CC through direct binding to substrates or by functioning as the essential
CC RING domain subunit of larger E3 complexes. Triggers the ubiquitin-
CC mediated degradation of many substrates, including proteins involved in
CC transcription regulation (ELL2, MYB, POU2AF1, PML and RBBP8), a cell
CC surface receptor (DCC), the cell-surface receptor-type tyrosine kinase
CC FLT3, the cytoplasmic signal transduction molecules (KLF10/TIEG1 and
CC NUMB), an antiapoptotic protein (BAG1), a microtubule motor protein
CC (KIF22), a protein involved in synaptic vesicle function in neurons
CC (SYP), a structural protein (CTNNB1) and SNCAIP. Confers constitutive
CC instability to HIPK2 through proteasomal degradation. It is thereby
CC involved in many cellular processes such as apoptosis, tumor
CC suppression, cell cycle, axon guidance, transcription regulation,
CC spermatogenesis and TNF-alpha signaling. Has some overlapping function
CC with SIAH2 (By similarity). Required for completion of meiosis I in
CC males (PubMed:11884614). Induces apoptosis in cooperation with PEG3
CC (PubMed:10681424). Upon nitric oxid (NO) generation that follows
CC apoptotic stimulation, interacts with S-nitrosylated GAPDH, mediating
CC the translocation of GAPDH to the nucleus. GAPDH acts as a stabilizer
CC of SIAH1, facilitating the degradation of nuclear proteins (By
CC similarity). Mediates ubiquitination and degradation of EGLN2 and EGLN3
CC in response to the unfolded protein response (UPR), leading to their
CC degradation and subsequent stabilization of ATF4 (PubMed:24809345).
CC Also part of the Wnt signaling pathway in which it mediates the Wnt-
CC induced ubiquitin-mediated proteasomal degradation of AXIN1.
CC {ECO:0000250|UniProtKB:Q8IUQ4, ECO:0000250|UniProtKB:Q920M9,
CC ECO:0000269|PubMed:10681424, ECO:0000269|PubMed:11884614,
CC ECO:0000269|PubMed:24809345, ECO:0000269|PubMed:28546513}.
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:28546513};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:28546513}.
CC -!- SUBUNIT: Homodimer. Component of some large E3 complex composed of
CC UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with UBE2I.
CC Interacts with alpha-tubulin. Interacts with PEG10, which may inhibit
CC its activity. Interacts with PEG3 and HIPK2 (By similarity). Interacts
CC with group 1 glutamate receptors GRM1 and GRM5. Interacts with DAB1,
CC which may inhibit its activity. Interacts with UBE2E2. Interacts with
CC SNCAIP. Interacts with GAPDH; leading to stabilize SIAH1. Interacts
CC with Bassoon/BSN and Piccolo/PLCO; these interactions negatively
CC regulate SIAH1 E3 ligase activity. Interacts with DCC (By similarity).
CC Interacts with AXIN1; catalyzes AXIN1 ubiquitination and subsequent
CC proteasome-mediated ubiquitin-dependent degradation.
CC {ECO:0000250|UniProtKB:Q8IUQ4, ECO:0000250|UniProtKB:Q920M9,
CC ECO:0000269|PubMed:10681424, ECO:0000269|PubMed:11742346,
CC ECO:0000269|PubMed:12646221, ECO:0000269|PubMed:16615911}.
CC -!- INTERACTION:
CC P61092; P97318: Dab1; NbExp=3; IntAct=EBI-446761, EBI-81680;
CC P61092; Q27934: phyl; Xeno; NbExp=2; IntAct=EBI-446761, EBI-77033;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Predominantly
CC cytoplasmic. Partially nuclear.
CC -!- TISSUE SPECIFICITY: Widely expressed at low level in embryos and
CC adults. Expressed at higher level in testis. Due to the high similarity
CC between SIAH1A and SIAH1B, it is difficult to distinguish its own
CC tissue specificity. {ECO:0000269|PubMed:8404535}.
CC -!- INDUCTION: May be induced by p53/TP53, suggesting that it may be
CC required to modulate p53/TP53 response (PubMed:12417719). The relevance
CC of such activity in vivo is however unclear and may not exist
CC (PubMed:12417719). Induced by ATF4 in response to the unfolded protein
CC response (UPR) (PubMed:24809345). {ECO:0000269|PubMed:12417719,
CC ECO:0000269|PubMed:24809345}.
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:0000269|PubMed:11742346}.
CC -!- PTM: Phosphorylated on Ser-19 by ATM and ATR. This phosphorylation
CC disrupts SIAH1 interaction with HIPK2, and subsequent proteasomal
CC degradation of HIPK2 (By similarity). {ECO:0000250|UniProtKB:Q8IUQ4}.
CC -!- SIMILARITY: Belongs to the SINA (Seven in absentia) family.
CC {ECO:0000305}.
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DR EMBL; Z19579; CAA79630.1; -; mRNA.
DR EMBL; BC046317; AAH46317.1; -; mRNA.
DR CCDS; CCDS22504.1; -.
DR PIR; I48763; I48763.
DR RefSeq; NP_033198.1; NM_009172.2.
DR RefSeq; XP_006530847.2; XM_006530784.3.
DR PDB; 1K2F; X-ray; 2.60 A; A/B=93-282.
DR PDB; 2AN6; X-ray; 3.00 A; A/B/C/D=92-282.
DR PDBsum; 1K2F; -.
DR PDBsum; 2AN6; -.
DR AlphaFoldDB; P61092; -.
DR SMR; P61092; -.
DR BioGRID; 203231; 8.
DR DIP; DIP-29100N; -.
DR IntAct; P61092; 4.
DR STRING; 10090.ENSMUSP00000044123; -.
DR PhosphoSitePlus; P61092; -.
DR EPD; P61092; -.
DR MaxQB; P61092; -.
DR PaxDb; P61092; -.
DR PRIDE; P61092; -.
DR ProteomicsDB; 257230; -.
DR DNASU; 20437; -.
DR Ensembl; ENSMUST00000045296; ENSMUSP00000044123; ENSMUSG00000036840.
DR GeneID; 20437; -.
DR KEGG; mmu:20437; -.
DR UCSC; uc009mqn.2; mouse.
DR CTD; 20437; -.
DR MGI; MGI:108064; Siah1a.
DR VEuPathDB; HostDB:ENSMUSG00000036840; -.
DR eggNOG; KOG3002; Eukaryota.
DR GeneTree; ENSGT00940000154837; -.
DR HOGENOM; CLU_028215_0_0_1; -.
DR InParanoid; P61092; -.
DR OMA; ADHEDAC; -.
DR OrthoDB; 780610at2759; -.
DR PhylomeDB; P61092; -.
DR TreeFam; TF312976; -.
DR Reactome; R-MMU-373752; Netrin-1 signaling.
DR Reactome; R-MMU-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 20437; 6 hits in 72 CRISPR screens.
DR ChiTaRS; Siah1a; mouse.
DR EvolutionaryTrace; P61092; -.
DR PRO; PR:P61092; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; P61092; protein.
DR Bgee; ENSMUSG00000036840; Expressed in secondary oocyte and 247 other tissues.
DR Genevisible; P61092; MM.
DR GO; GO:0030877; C:beta-catenin destruction complex; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005769; C:early endosome; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IMP:CAFA.
DR GO; GO:0097718; F:disordered domain specific binding; IPI:CAFA.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0008022; F:protein C-terminus binding; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:UniProtKB.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IBA:GO_Central.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IMP:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0060070; P:canonical Wnt signaling pathway; IMP:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0007141; P:male meiosis I; IMP:MGI.
DR GO; GO:0051402; P:neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0009791; P:post-embryonic development; IMP:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR GO; GO:0031648; P:protein destabilization; ISO:MGI.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0007283; P:spermatogenesis; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA: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 3D-structure; Apoptosis; Cell cycle; Cytoplasm; Developmental protein;
KW Differentiation; Metal-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Spermatogenesis; Transferase; Ubl conjugation pathway;
KW Zinc; Zinc-finger.
FT CHAIN 1..282
FT /note="E3 ubiquitin-protein ligase SIAH1A"
FT /id="PRO_0000056164"
FT ZN_FING 41..76
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 93..153
FT /note="SIAH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00455"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 90..282
FT /note="SBD"
FT /evidence="ECO:0000269|PubMed:11742346"
FT BINDING 98
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 105
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 117
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 121
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 128
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 135
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 147
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT BINDING 152
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:11742346,
FT ECO:0000269|PubMed:16615911"
FT MOD_RES 19
FT /note="Phosphoserine; by ATM and ATR"
FT /evidence="ECO:0000250|UniProtKB:Q8IUQ4"
FT MUTAGEN 156
FT /note="T->E: Strongly reduced binding and degradation of
FT target proteins; when associated with D-158."
FT /evidence="ECO:0000269|PubMed:16615911"
FT MUTAGEN 158
FT /note="L->D,K: Strongly reduced binding of target proteins.
FT Strongly reduced degradation of target proteins."
FT /evidence="ECO:0000269|PubMed:16615911"
FT MUTAGEN 166
FT /note="L->K: Minor effect on binding and degradation of
FT target proteins."
FT /evidence="ECO:0000269|PubMed:16615911"
FT MUTAGEN 176..178
FT /note="VDW->AAA: Loss of interaction with AXIN1. Loss of
FT function in AXIN1 degradation. Loss of function in Wnt
FT signaling."
FT /evidence="ECO:0000269|PubMed:28546513"
FT MUTAGEN 180
FT /note="M->K: Strongly reduced binding of target proteins.
FT Strongly reduced degradation of target proteins."
FT /evidence="ECO:0000269|PubMed:16615911"
FT HELIX 101..103
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 111..113
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 114..119
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 130..132
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 141..143
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 144..150
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 156..167
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 177..184
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 187..198
FT /evidence="ECO:0007829|PDB:1K2F"
FT TURN 199..201
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 202..213
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 221..229
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 232..238
FT /evidence="ECO:0007829|PDB:1K2F"
FT TURN 243..245
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 248..252
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 256..260
FT /evidence="ECO:0007829|PDB:1K2F"
FT HELIX 261..267
FT /evidence="ECO:0007829|PDB:1K2F"
FT STRAND 272..281
FT /evidence="ECO:0007829|PDB:1K2F"
SQ SEQUENCE 282 AA; 31137 MW; 852EADC5DD4A4FFA CRC64;
MSRQTATALP TGTSKCPPSQ RVPALTGTTA SNNDLASLFE CPVCFDYVLP PILQCQSGHL
VCSNCRPKLT CCPTCRGPLG SIRNLAMEKV ANSVLFPCKY ASSGCEITLP HTEKAEHEEL
CEFRPYSCPC PGASCKWQGS LDAVMPHLMH QHKSITTLQG EDIVFLATDI NLPGAVDWVM
MQSCFGFHFM LVLEKQEKYD GHQQFFAIVQ LIGTRKQAEN FAYRLELNGH RRRLTWEATP
RSIHEGIATA IMNSDCLVFD TSIAQLFAEN GNLGINVTIS MC
