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Q91WA6 (SHRPN_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 87. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Sharpin
Alternative name(s):
Shank-associated RH domain-interacting protein
Shank-interacting protein-like 1
Short name=mSIPL1
Gene names
Name:Sharpin
Synonyms:Cpdm, Sipl1
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length380 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of the LUBAC complex which conjugates linear polyubiquitin chains in a head-to-tail manner to substrates and plays a key role in NF-kappa-B activation and regulation of inflammation. LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in activation of the canonical NF-kappa-B and the JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interferes with TNF-induced cell death and thereby prevents inflammation. LUBAC is proposed to be recruited to the TNF-R1 signaling complex (TNF-RSC) following polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 and to conjugate linear polyubiquitin to IKBKG and possibly other components contributing to the stability of the complex. Together with FAM105B/otulin, the LUBAC complex regulates the canonical Wnt signaling during angiogenesis. Ref.3 Ref.8 Ref.9 Ref.10

Subunit structure

Monomer and homodimer. Component of the LUBAC complex (linear ubiquitin chain assembly complex) which consists of SHARPIN, RBCK1 and RNF31. LUBAC has a MW of approximative 600 kDa suggesting a heteromultimeric assembly of its subunits. Associates with the TNF-R1 signaling complex (TNF-RSC) in a stimulation-dependent manner. Interacts with EYA1, EYA2, SHANK1 and SHANK3 (via ANK repeats). Ref.5

Subcellular location

Cytoplasmcytosol By similarity. Cell junctionsynapse By similarity. Note: Enriched at synaptic sites in mature neurons where it colocalizes with SHANK1 By similarity.

Tissue specificity

Highly expressed in thymus and spleen. Present at high level in splenic B- and T-cells (at protein level). Ref.9

Domain

The Ubiquitin-like domain is required for the interaction with RNF31 By similarity.

The RanBP2-type zinc fingers mediate the specific interaction with ubiquitin. Binds preferentially linear polyubiquitin chains and 'Lys-63'-linked polyubiquitin chains over 'Lys-48'-linked polyubiquitin chains. Also binds monoubiquitin By similarity.

Involvement in disease

Defects in Sharpin are the cause of chronic proliferative dermatitis (cpdm). Cpdm is a spontaneous mutation causing a chronic proliferative dermatitis phenotype, which is characterized histologically by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development. Mice also display lower total and cortical bone mineral content and bone mineral density, trabecular and cortical bone volume, and trabecular number. TNF-alpha-induced NF-kappa-B activation is attenuated due to inability of the LUBAC complex to mediate linear ubiquitination.

Sequence similarities

Contains 1 RanBP2-type zinc finger.

Contains 1 ubiquitin-like domain.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCell junction
Cytoplasm
Synapse
   Coding sequence diversityAlternative splicing
   DomainZinc-finger
   LigandMetal-binding
Zinc
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic nuclear changes

Inferred from mutant phenotype PubMed 7792947. Source: MGI

brain development

Inferred from electronic annotation. Source: Ensembl

epidermis development

Inferred from mutant phenotype PubMed 7792947. Source: MGI

keratinization

Inferred from mutant phenotype PubMed 7792947. Source: MGI

mitochondrion organization

Inferred from mutant phenotype PubMed 7792947. Source: MGI

negative regulation of inflammatory response

Inferred from mutant phenotype Ref.8Ref.9. Source: UniProtKB

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from mutant phenotype Ref.8Ref.9. Source: UniProtKB

protein homooligomerization

Inferred from electronic annotation. Source: Ensembl

protein linear polyubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of CD40 signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of tumor necrosis factor-mediated signaling pathway

Inferred from mutant phenotype Ref.8Ref.9. Source: UniProtKB

   Cellular_componentLUBAC complex

Inferred from sequence or structural similarity. Source: UniProtKB

cell junction

Inferred from electronic annotation. Source: UniProtKB-KW

cytosol

Inferred from sequence or structural similarity. Source: UniProtKB

dendrite

Inferred from electronic annotation. Source: Ensembl

postsynaptic density

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionpolyubiquitin binding

Inferred from sequence or structural similarity. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q91WA6-1)

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: Q91WA6-2)

The sequence of this isoform differs from the canonical sequence as follows:
     306-380: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 380380Sharpin
PRO_0000280635

Regions

Domain216 – 28570Ubiquitin-like
Zinc finger342 – 37130RanBP2-type
Region1 – 177177Self-association By similarity
Region172 – 305134Interaction with SHANK1 By similarity

Amino acid modifications

Modified residue1631Phosphoserine By similarity
Modified residue3071Phosphoserine By similarity

Natural variations

Alternative sequence306 – 38075Missing in isoform 2.
VSP_023839

Experimental info

Sequence conflict1311P → Q in BAC53796. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 1, 2001. Version 1.
Checksum: C7E4B8F40F6D8F05

FASTA38039,852
        10         20         30         40         50         60 
MSPPAGGAAV AADPASPVVL LAVHAAVRPL GAGQDAEAQP RKLQLIADPE RPGRFRLGLL 

        70         80         90        100        110        120 
GTEPGAVSLE WPLEAICYTV RGPNQHELQP PPGGPGTFSV HFLDPEEAQQ WAALVRDATA 

       130        140        150        160        170        180 
EGQNGSGSPA PAPAPAMCPI SPPCSSMAQI PKATQPEVDL PQSSGNFKKE ELATRLSQAI 

       190        200        210        220        230        240 
AGGDEKAAAQ VAAVLAQHHV ALNVQLMEAW FPPGPIRLQV TVEDATSVLS SSSSAHVSLK 

       250        260        270        280        290        300 
IHPHCSIAAL QDQVFSEFGF PPAVQRWVIG RCLCMPERSL ASYGVSQDGD PAFLYLLSAP 

       310        320        330        340        350        360 
REVSGQSLQN SKMDRKLGLF PQSLGLPHDL QPSSSSLPSP SQPGWSCPSC TFINASNRPG 

       370        380 
CEMCSTQRPC AWDPLAAAST 

« Hide

Isoform 2 [UniParc].

Checksum: 6428AD468FC5BEF6
Show »

FASTA30531,864

References

« Hide 'large scale' references
[1]"Novel human and mouse genes encoding a shank-interacting protein and its upregulation in gastric fundus of W/WV mouse."
Daigo Y., Takayama I., Ward S.M., Sanders K.M., Fujino M.A.
J. Gastroenterol. Hepatol. 18:712-718(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
Strain: C57BL/6.
Tissue: Brain and Eye.
[3]"Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis."
Seymour R.E., Hasham M.G., Cox G.A., Shultz L.D., Hogenesch H., Roopenian D.C., Sundberg J.P.
Genes Immun. 8:416-421(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INVOLVEMENT IN CPDM.
[4]"Anti-IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin-deficient mice."
Renninger M.L., Seymour R.E., Whiteley L.O., Sundberg J.P., Hogenesch H.
Exp. Dermatol. 19:252-258(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CPDM.
[5]"Sipl1 and Rbck1 are novel Eya1-binding proteins with a role in craniofacial development."
Landgraf K., Bollig F., Trowe M.O., Besenbeck B., Ebert C., Kruspe D., Kispert A., Hanel F., Englert C.
Mol. Cell. Biol. 30:5764-5775(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH EYA1 AND EYA2.
[6]"Loss-of-function of SHARPIN causes an osteopenic phenotype in mice."
Xia T., Liang Y., Ma J., Li M., Gong M., Yu X.
Endocrine 39:104-112(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CPDM.
[7]"Inhibition of NF-kappaB signaling retards eosinophilic dermatitis in SHARPIN-deficient mice."
Liang Y., Seymour R.E., Sundberg J.P.
J. Invest. Dermatol. 131:141-149(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CPDM.
[8]"Linear ubiquitination prevents inflammation and regulates immune signalling."
Gerlach B., Cordier S.M., Schmukle A.C., Emmerich C.H., Rieser E., Haas T.L., Webb A.I., Rickard J.A., Anderton H., Wong W.W., Nachbur U., Gangoda L., Warnken U., Purcell A.W., Silke J., Walczak H.
Nature 471:591-596(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INVOLVEMENT IN CPDM.
[9]"SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex."
Tokunaga F., Nakagawa T., Nakahara M., Saeki Y., Taniguchi M., Sakata S., Tanaka K., Nakano H., Iwai K.
Nature 471:633-636(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INVOLVEMENT IN CPDM, TISSUE SPECIFICITY.
[10]"SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis."
Ikeda F., Deribe Y.L., Skanland S.S., Stieglitz B., Grabbe C., Franz-Wachtel M., van Wijk S.J., Goswami P., Nagy V., Terzic J., Tokunaga F., Androulidaki A., Nakagawa T., Pasparakis M., Iwai K., Sundberg J.P., Schaefer L., Rittinger K., Macek B., Dikic I.
Nature 471:637-641(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INVOLVEMENT IN CPDM.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB052763 mRNA. Translation: BAC53796.1.
BC016203 mRNA. Translation: AAH16203.1.
BC055758 mRNA. Translation: AAH55758.1.
RefSeqNP_079616.2. NM_025340.2.
UniGeneMm.41463.

3D structure databases

ProteinModelPortalQ91WA6.
SMRQ91WA6. Positions 19-119, 214-299, 342-373.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid222977. 23 interactions.
DIPDIP-49461N.
IntActQ91WA6. 3 interactions.

PTM databases

PhosphoSiteQ91WA6.

Proteomic databases

PaxDbQ91WA6.
PRIDEQ91WA6.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000023211; ENSMUSP00000023211; ENSMUSG00000022552. [Q91WA6-1]
GeneID106025.
KEGGmmu:106025.
UCSCuc007wju.2. mouse. [Q91WA6-1]

Organism-specific databases

CTD81858.
MGIMGI:1913331. Sharpin.

Phylogenomic databases

eggNOGNOG278522.
GeneTreeENSGT00530000063620.
HOGENOMHOG000095521.
HOVERGENHBG093954.
InParanoidQ91WA6.
OMAHELQPPP.
OrthoDBEOG7T7GTX.
PhylomeDBQ91WA6.
TreeFamTF323486.

Gene expression databases

ArrayExpressQ91WA6.
BgeeQ91WA6.
CleanExMM_SHARPIN.
GenevestigatorQ91WA6.

Family and domain databases

InterProIPR026168. SHARPIN.
IPR001876. Znf_RanBP2.
[Graphical view]
PANTHERPTHR22770:SF11. PTHR22770:SF11. 1 hit.
PfamPF00641. zf-RanBP. 1 hit.
[Graphical view]
SMARTSM00547. ZnF_RBZ. 1 hit.
[Graphical view]
PROSITEPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio358020.
PROQ91WA6.
SOURCESearch...

Entry information

Entry nameSHRPN_MOUSE
AccessionPrimary (citable) accession number: Q91WA6
Secondary accession number(s): Q7TNT3, Q8CHL3
Entry history
Integrated into UniProtKB/Swiss-Prot: March 20, 2007
Last sequence update: December 1, 2001
Last modified: April 16, 2014
This is version 87 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot