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Protein

Sharpin

Gene

Sharpin

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.4 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri342 – 371RanBP2-typePROSITE-ProRule annotationAdd BLAST30

GO - Molecular functioni

GO - Biological processi

  • apoptotic nuclear changes Source: MGI
  • brain development Source: Ensembl
  • epidermis development Source: MGI
  • keratinization Source: MGI
  • mitochondrion organization Source: MGI
  • negative regulation of inflammatory response Source: UniProtKB
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  • proteasome-mediated ubiquitin-dependent protein catabolic process Source: GO_Central
  • protein homooligomerization Source: Ensembl
  • protein linear polyubiquitination Source: UniProtKB
  • regulation of CD40 signaling pathway Source: UniProtKB
  • regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB

Keywordsi

Biological processUbl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-5357905 Regulation of TNFR1 signaling
R-MMU-5357956 TNFR1-induced NFkappaB signaling pathway

Names & Taxonomyi

Protein namesi
Recommended name:
Sharpin
Alternative name(s):
Shank-associated RH domain-interacting protein
Shank-interacting protein-like 1
Short name:
mSIPL1
Gene namesi
Name:Sharpin
Synonyms:Cpdm, Sipl1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 15

Organism-specific databases

MGIiMGI:1913331 Sharpin

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell junction, Cytoplasm, Synapse

Pathology & Biotechi

Involvement in diseasei

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.7 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002806351 – 380SharpinAdd BLAST380

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei163PhosphoserineBy similarity1
Modified residuei307PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ91WA6
PaxDbiQ91WA6
PeptideAtlasiQ91WA6
PRIDEiQ91WA6

PTM databases

iPTMnetiQ91WA6
PhosphoSitePlusiQ91WA6

Expressioni

Tissue specificityi

Highly expressed in thymus and spleen. Present at high level in splenic B- and T-cells (at protein level).1 Publication

Gene expression databases

BgeeiENSMUSG00000022552
CleanExiMM_SHARPIN
ExpressionAtlasiQ91WA6 baseline and differential
GenevisibleiQ91WA6 MM

Interactioni

Subunit structurei

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 approximately 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).1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi222977, 23 interactors
DIPiDIP-49461N
IntActiQ91WA6, 6 interactors
MINTiQ91WA6
STRINGi10090.ENSMUSP00000023211

Structurei

3D structure databases

ProteinModelPortaliQ91WA6
SMRiQ91WA6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini216 – 285Ubiquitin-likeAdd BLAST70

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 177Self-associationBy similarityAdd BLAST177
Regioni172 – 305Interaction with SHANK1By similarityAdd BLAST134

Domaini

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).By similarity

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri342 – 371RanBP2-typePROSITE-ProRule annotationAdd BLAST30

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG1815 Eukaryota
ENOG410XP9Y LUCA
GeneTreeiENSGT00530000063620
HOGENOMiHOG000095521
HOVERGENiHBG093954
InParanoidiQ91WA6
KOiK20894
OMAiCEMCSTQ
OrthoDBiEOG091G0GY5
PhylomeDBiQ91WA6
TreeFamiTF323486

Family and domain databases

Gene3Di2.30.29.30, 1 hit
InterProiView protein in InterPro
IPR011993 PH-like_dom_sf
IPR026168 SHARPIN
IPR031912 Sharpin_PH
IPR029071 Ubiquitin-like_domsf
IPR001876 Znf_RanBP2
IPR036443 Znf_RanBP2_sf
PANTHERiPTHR22770:SF36 PTHR22770:SF36, 1 hit
PfamiView protein in Pfam
PF16764 Sharpin_PH, 1 hit
SMARTiView protein in SMART
SM00547 ZnF_RBZ, 1 hit
SUPFAMiSSF54236 SSF54236, 1 hit
SSF90209 SSF90209, 1 hit
PROSITEiView protein in PROSITE
PS01358 ZF_RANBP2_1, 1 hit
PS50199 ZF_RANBP2_2, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q91WA6-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MSPPAGGAAV AADPASPVVL LAVHAAVRPL GAGQDAEAQP RKLQLIADPE
60 70 80 90 100
RPGRFRLGLL GTEPGAVSLE WPLEAICYTV RGPNQHELQP PPGGPGTFSV
110 120 130 140 150
HFLDPEEAQQ WAALVRDATA EGQNGSGSPA PAPAPAMCPI SPPCSSMAQI
160 170 180 190 200
PKATQPEVDL PQSSGNFKKE ELATRLSQAI AGGDEKAAAQ VAAVLAQHHV
210 220 230 240 250
ALNVQLMEAW FPPGPIRLQV TVEDATSVLS SSSSAHVSLK IHPHCSIAAL
260 270 280 290 300
QDQVFSEFGF PPAVQRWVIG RCLCMPERSL ASYGVSQDGD PAFLYLLSAP
310 320 330 340 350
REVSGQSLQN SKMDRKLGLF PQSLGLPHDL QPSSSSLPSP SQPGWSCPSC
360 370 380
TFINASNRPG CEMCSTQRPC AWDPLAAAST
Length:380
Mass (Da):39,852
Last modified:December 1, 2001 - v1
Checksum:iC7E4B8F40F6D8F05
GO
Isoform 2 (identifier: Q91WA6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     306-380: Missing.

Note: No experimental confirmation available.
Show »
Length:305
Mass (Da):31,864
Checksum:i6428AD468FC5BEF6
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti131P → Q in BAC53796 (PubMed:12753155).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_023839306 – 380Missing in isoform 2. 1 PublicationAdd BLAST75

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB052763 mRNA Translation: BAC53796.1
BC016203 mRNA Translation: AAH16203.1
BC055758 mRNA Translation: AAH55758.1
CCDSiCCDS37121.1 [Q91WA6-1]
RefSeqiNP_079616.2, NM_025340.2 [Q91WA6-1]
UniGeneiMm.41463

Genome annotation databases

EnsembliENSMUST00000023211; ENSMUSP00000023211; ENSMUSG00000022552 [Q91WA6-1]
GeneIDi106025
KEGGimmu:106025
UCSCiuc007wju.2 mouse [Q91WA6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiSHRPN_MOUSE
AccessioniPrimary (citable) accession number: Q91WA6
Secondary accession number(s): Q7TNT3, Q8CHL3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 20, 2007
Last sequence update: December 1, 2001
Last modified: April 25, 2018
This is version 123 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health