SHRPN_MOUSE
ID SHRPN_MOUSE Reviewed; 380 AA.
AC Q91WA6; Q7TNT3; Q8CHL3;
DT 20-MAR-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 149.
DE RecName: Full=Sharpin;
DE AltName: Full=Shank-associated RH domain-interacting protein;
DE AltName: Full=Shank-interacting protein-like 1;
DE Short=mSIPL1;
GN Name=Sharpin; Synonyms=Cpdm, Sipl1;
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] (ISOFORM 1).
RX PubMed=12753155; DOI=10.1046/j.1440-1746.2003.03046.x;
RA Daigo Y., Takayama I., Ward S.M., Sanders K.M., Fujino M.A.;
RT "Novel human and mouse genes encoding a shank-interacting protein and its
RT upregulation in gastric fundus of W/WV mouse.";
RL J. Gastroenterol. Hepatol. 18:712-718(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J; TISSUE=Brain, and Eye;
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 INVOLVEMENT IN CPDM.
RX PubMed=17538631; DOI=10.1038/sj.gene.6364403;
RA Seymour R.E., Hasham M.G., Cox G.A., Shultz L.D., Hogenesch H.,
RA Roopenian D.C., Sundberg J.P.;
RT "Spontaneous mutations in the mouse Sharpin gene result in multiorgan
RT inflammation, immune system dysregulation and dermatitis.";
RL Genes Immun. 8:416-421(2007).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP INVOLVEMENT IN CPDM.
RX PubMed=19650867; DOI=10.1111/j.1600-0625.2009.00944.x;
RA Renninger M.L., Seymour R.E., Whiteley L.O., Sundberg J.P., Hogenesch H.;
RT "Anti-IL5 decreases the number of eosinophils but not the severity of
RT dermatitis in Sharpin-deficient mice.";
RL Exp. Dermatol. 19:252-258(2010).
RN [6]
RP INTERACTION WITH EYA1 AND EYA2.
RX PubMed=20956555; DOI=10.1128/mcb.01645-09;
RA Landgraf K., Bollig F., Trowe M.O., Besenbeck B., Ebert C., Kruspe D.,
RA Kispert A., Hanel F., Englert C.;
RT "Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in
RT craniofacial development.";
RL Mol. Cell. Biol. 30:5764-5775(2010).
RN [7]
RP INVOLVEMENT IN CPDM.
RX PubMed=21069580; DOI=10.1007/s12020-010-9418-1;
RA Xia T., Liang Y., Ma J., Li M., Gong M., Yu X.;
RT "Loss-of-function of SHARPIN causes an osteopenic phenotype in mice.";
RL Endocrine 39:104-112(2011).
RN [8]
RP INVOLVEMENT IN CPDM.
RX PubMed=20811394; DOI=10.1038/jid.2010.259;
RA Liang Y., Seymour R.E., Sundberg J.P.;
RT "Inhibition of NF-kappaB signaling retards eosinophilic dermatitis in
RT SHARPIN-deficient mice.";
RL J. Invest. Dermatol. 131:141-149(2011).
RN [9]
RP FUNCTION, AND INVOLVEMENT IN CPDM.
RX PubMed=21455173; DOI=10.1038/nature09816;
RA Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E.,
RA Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U.,
RA Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H.;
RT "Linear ubiquitination prevents inflammation and regulates immune
RT signalling.";
RL Nature 471:591-596(2011).
RN [10]
RP FUNCTION, INVOLVEMENT IN CPDM, AND TISSUE SPECIFICITY.
RX PubMed=21455180; DOI=10.1038/nature09815;
RA Tokunaga F., Nakagawa T., Nakahara M., Saeki Y., Taniguchi M., Sakata S.,
RA Tanaka K., Nakano H., Iwai K.;
RT "SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain
RT assembly complex.";
RL Nature 471:633-636(2011).
RN [11]
RP FUNCTION, AND INVOLVEMENT IN CPDM.
RX PubMed=21455181; DOI=10.1038/nature09814;
RA Ikeda F., Deribe Y.L., Skanland S.S., Stieglitz B., Grabbe C.,
RA Franz-Wachtel M., van Wijk S.J., Goswami P., Nagy V., Terzic J.,
RA Tokunaga F., Androulidaki A., Nakagawa T., Pasparakis M., Iwai K.,
RA Sundberg J.P., Schaefer L., Rittinger K., Macek B., Dikic I.;
RT "SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB
RT activity and apoptosis.";
RL Nature 471:637-641(2011).
CC -!- FUNCTION: Component of the LUBAC complex which conjugates linear
CC polyubiquitin chains in a head-to-tail manner to substrates and plays a
CC key role in NF-kappa-B activation and regulation of inflammation
CC (PubMed:17538631, PubMed:21455173, PubMed:21455180, PubMed:21455181).
CC LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is
CC involved in activation of the canonical NF-kappa-B and the JNK
CC signaling pathways (PubMed:17538631, PubMed:21455173, PubMed:21455180,
CC PubMed:21455181). Linear ubiquitination mediated by the LUBAC complex
CC interferes with TNF-induced cell death and thereby prevents
CC inflammation (PubMed:17538631, PubMed:21455173, PubMed:21455180,
CC PubMed:21455181). LUBAC is recruited to the TNF-R1 signaling complex
CC (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2
CC and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and
CC possibly other components contributing to the stability of the complex.
CC The LUBAC complex is also involved in innate immunity by conjugating
CC linear polyubiquitin chains at the surface of bacteria invading the
CC cytosol to form the ubiquitin coat surrounding bacteria. LUBAC is not
CC able to initiate formation of the bacterial ubiquitin coat, and can
CC only promote formation of linear polyubiquitins on pre-existing
CC ubiquitin. The bacterial ubiquitin coat acts as an 'eat-me' signal for
CC xenophagy and promotes NF-kappa-B activation. Together with OTULIN, the
CC LUBAC complex regulates the canonical Wnt signaling during angiogenesis
CC (By similarity). {ECO:0000250|UniProtKB:Q9H0F6,
CC ECO:0000269|PubMed:17538631, ECO:0000269|PubMed:21455173,
CC ECO:0000269|PubMed:21455180, ECO:0000269|PubMed:21455181}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q9H0F6}.
CC -!- SUBUNIT: Monomer and homodimer (By similarity). Component of the LUBAC
CC complex (linear ubiquitin chain assembly complex) which consists of
CC SHARPIN, RBCK1 and RNF31 (By similarity). LUBAC has a MW of
CC approximately 600 kDa suggesting a heteromultimeric assembly of its
CC subunits (By similarity). Associates with the TNF-R1 signaling complex
CC (TNF-RSC) in a stimulation-dependent manner (By similarity). Interacts
CC with EYA1, EYA2, SHANK1 and SHANK3 (via ANK repeats) (PubMed:20956555).
CC {ECO:0000250|UniProtKB:Q9EQL9, ECO:0000250|UniProtKB:Q9H0F6,
CC ECO:0000269|PubMed:20956555}.
CC -!- INTERACTION:
CC Q91WA6; P97767: Eya1; NbExp=4; IntAct=EBI-646097, EBI-1368503;
CC Q91WA6; O08575: Eya2; NbExp=2; IntAct=EBI-646097, EBI-986503;
CC Q91WA6; Q924T7: Rnf31; NbExp=10; IntAct=EBI-646097, EBI-647680;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9H0F6}. Synapse {ECO:0000250|UniProtKB:Q9EQL9}.
CC Note=Enriched at synaptic sites in mature neurons where it colocalizes
CC with SHANK1. {ECO:0000250|UniProtKB:Q9EQL9}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q91WA6-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91WA6-2; Sequence=VSP_023839;
CC -!- TISSUE SPECIFICITY: Highly expressed in thymus and spleen. Present at
CC high level in splenic B- and T-cells (at protein level).
CC {ECO:0000269|PubMed:21455180}.
CC -!- DOMAIN: The Ubiquitin-like domain is required for the interaction with
CC RNF31. {ECO:0000250|UniProtKB:Q9H0F6}.
CC -!- DOMAIN: The RanBP2-type zinc fingers mediate the specific interaction
CC with ubiquitin. Binds preferentially linear polyubiquitin chains and
CC 'Lys-63'-linked polyubiquitin chains over 'Lys-48'-linked polyubiquitin
CC chains. Also binds monoubiquitin (By similarity).
CC {ECO:0000250|UniProtKB:Q9H0F6}.
CC -!- DISEASE: Note=Defects in Sharpin are the cause of chronic proliferative
CC dermatitis (cpdm). Cpdm is a spontaneous mutation causing a chronic
CC proliferative dermatitis phenotype, which is characterized
CC histologically by severe inflammation, eosinophilic dermatitis and
CC defects in secondary lymphoid organ development. Mice also display
CC lower total and cortical bone mineral content and bone mineral density,
CC trabecular and cortical bone volume, and trabecular number. TNF-alpha-
CC induced NF-kappa-B activation is attenuated due to inability of the
CC LUBAC complex to mediate linear ubiquitination.
CC {ECO:0000269|PubMed:17538631, ECO:0000269|PubMed:19650867,
CC ECO:0000269|PubMed:20811394, ECO:0000269|PubMed:21069580,
CC ECO:0000269|PubMed:21455173, ECO:0000269|PubMed:21455180,
CC ECO:0000269|PubMed:21455181}.
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DR EMBL; AB052763; BAC53796.1; -; mRNA.
DR EMBL; BC016203; AAH16203.1; -; mRNA.
DR EMBL; BC055758; AAH55758.1; -; mRNA.
DR CCDS; CCDS37121.1; -. [Q91WA6-1]
DR RefSeq; NP_079616.2; NM_025340.2. [Q91WA6-1]
DR PDB; 5Y3T; X-ray; 2.40 A; C=163-341.
DR PDBsum; 5Y3T; -.
DR AlphaFoldDB; Q91WA6; -.
DR SMR; Q91WA6; -.
DR BioGRID; 222977; 27.
DR DIP; DIP-49461N; -.
DR IntAct; Q91WA6; 6.
DR MINT; Q91WA6; -.
DR STRING; 10090.ENSMUSP00000023211; -.
DR iPTMnet; Q91WA6; -.
DR PhosphoSitePlus; Q91WA6; -.
DR EPD; Q91WA6; -.
DR MaxQB; Q91WA6; -.
DR PaxDb; Q91WA6; -.
DR PeptideAtlas; Q91WA6; -.
DR PRIDE; Q91WA6; -.
DR ProteomicsDB; 261356; -. [Q91WA6-1]
DR ProteomicsDB; 261357; -. [Q91WA6-2]
DR Antibodypedia; 7700; 272 antibodies from 30 providers.
DR Ensembl; ENSMUST00000023211; ENSMUSP00000023211; ENSMUSG00000022552. [Q91WA6-1]
DR GeneID; 106025; -.
DR KEGG; mmu:106025; -.
DR UCSC; uc007wju.2; mouse. [Q91WA6-1]
DR CTD; 81858; -.
DR MGI; MGI:1913331; Sharpin.
DR VEuPathDB; HostDB:ENSMUSG00000022552; -.
DR eggNOG; KOG1815; Eukaryota.
DR GeneTree; ENSGT00940000161574; -.
DR HOGENOM; CLU_014998_0_1_1; -.
DR InParanoid; Q91WA6; -.
DR OMA; TQQTEWA; -.
DR OrthoDB; 1086223at2759; -.
DR PhylomeDB; Q91WA6; -.
DR TreeFam; TF323486; -.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-5357956; TNFR1-induced NFkappaB signaling pathway.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 106025; 18 hits in 78 CRISPR screens.
DR ChiTaRS; Sharpin; mouse.
DR PRO; PR:Q91WA6; -.
DR Proteomes; UP000000589; Chromosome 15.
DR RNAct; Q91WA6; protein.
DR Bgee; ENSMUSG00000022552; Expressed in external carotid artery and 260 other tissues.
DR ExpressionAtlas; Q91WA6; baseline and differential.
DR Genevisible; Q91WA6; MM.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0071797; C:LUBAC complex; ISS:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISO:MGI.
DR GO; GO:0000151; C:ubiquitin ligase complex; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031593; F:polyubiquitin modification-dependent protein binding; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0043130; F:ubiquitin binding; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IBA:GO_Central.
DR GO; GO:0030262; P:apoptotic nuclear changes; IMP:MGI.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; ISS:UniProtKB.
DR GO; GO:0008544; P:epidermis development; IMP:MGI.
DR GO; GO:0031424; P:keratinization; IMP:MGI.
DR GO; GO:0007005; P:mitochondrion organization; IMP:MGI.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central.
DR GO; GO:0097039; P:protein linear polyubiquitination; ISS:UniProtKB.
DR GO; GO:2000348; P:regulation of CD40 signaling pathway; ISS:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR DisProt; DP02805; -.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR026261; RBCK1/SHARPIN.
DR InterPro; IPR031912; Sharpin_PH.
DR InterPro; IPR029071; Ubiquitin-like_domsf.
DR InterPro; IPR001876; Znf_RanBP2.
DR InterPro; IPR036443; Znf_RanBP2_sf.
DR PANTHER; PTHR22770:SF43; PTHR22770:SF43; 1.
DR Pfam; PF16764; Sharpin_PH; 1.
DR SMART; SM00547; ZnF_RBZ; 1.
DR SUPFAM; SSF54236; SSF54236; 1.
DR SUPFAM; SSF90209; SSF90209; 1.
DR PROSITE; PS01358; ZF_RANBP2_1; 1.
DR PROSITE; PS50199; ZF_RANBP2_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Metal-binding;
KW Phosphoprotein; Reference proteome; Synapse; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..380
FT /note="Sharpin"
FT /id="PRO_0000280635"
FT DOMAIN 216..285
FT /note="Ubiquitin-like"
FT ZN_FING 342..371
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT REGION 1..177
FT /note="Self-association"
FT /evidence="ECO:0000250|UniProtKB:Q9EQL9"
FT REGION 172..305
FT /note="Interaction with SHANK1"
FT /evidence="ECO:0000250|UniProtKB:Q9EQL9"
FT MOD_RES 163
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9H0F6"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9H0F6"
FT VAR_SEQ 306..380
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_023839"
FT CONFLICT 131
FT /note="P -> Q (in Ref. 1; BAC53796)"
FT /evidence="ECO:0000305"
FT HELIX 170..182
FT /evidence="ECO:0007829|PDB:5Y3T"
FT HELIX 185..197
FT /evidence="ECO:0007829|PDB:5Y3T"
FT STRAND 202..206
FT /evidence="ECO:0007829|PDB:5Y3T"
FT HELIX 208..210
FT /evidence="ECO:0007829|PDB:5Y3T"
FT STRAND 216..223
FT /evidence="ECO:0007829|PDB:5Y3T"
FT STRAND 236..241
FT /evidence="ECO:0007829|PDB:5Y3T"
FT HELIX 247..258
FT /evidence="ECO:0007829|PDB:5Y3T"
FT HELIX 262..264
FT /evidence="ECO:0007829|PDB:5Y3T"
FT STRAND 265..269
FT /evidence="ECO:0007829|PDB:5Y3T"
FT HELIX 281..283
FT /evidence="ECO:0007829|PDB:5Y3T"
FT STRAND 291..296
FT /evidence="ECO:0007829|PDB:5Y3T"
SQ SEQUENCE 380 AA; 39852 MW; C7E4B8F40F6D8F05 CRC64;
MSPPAGGAAV AADPASPVVL LAVHAAVRPL GAGQDAEAQP RKLQLIADPE RPGRFRLGLL
GTEPGAVSLE WPLEAICYTV RGPNQHELQP PPGGPGTFSV HFLDPEEAQQ WAALVRDATA
EGQNGSGSPA PAPAPAMCPI SPPCSSMAQI PKATQPEVDL PQSSGNFKKE ELATRLSQAI
AGGDEKAAAQ VAAVLAQHHV ALNVQLMEAW FPPGPIRLQV TVEDATSVLS SSSSAHVSLK
IHPHCSIAAL QDQVFSEFGF PPAVQRWVIG RCLCMPERSL ASYGVSQDGD PAFLYLLSAP
REVSGQSLQN SKMDRKLGLF PQSLGLPHDL QPSSSSLPSP SQPGWSCPSC TFINASNRPG
CEMCSTQRPC AWDPLAAAST
