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Protein

Sharpin

Gene

SHARPIN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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.3 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri348 – 377RanBP2-typePROSITE-ProRule annotationAdd BLAST30

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-5357905. Regulation of TNFR1 signaling.
R-HSA-5357956. TNFR1-induced NFkappaB signaling pathway.
R-HSA-6794361. Interactions of neurexins and neuroligins at synapses.

Names & Taxonomyi

Protein namesi
Recommended name:
Sharpin
Alternative name(s):
Shank-associated RH domain-interacting protein
Shank-interacting protein-like 1
Short name:
hSIPL1
Gene namesi
Name:SHARPIN
Synonyms:SIPL1
ORF Names:PSEC0216
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

HGNCiHGNC:25321. SHARPIN.

Subcellular locationi

GO - Cellular componenti

  • cell junction Source: UniProtKB-KW
  • cytoplasm Source: HPA
  • cytosol Source: UniProtKB
  • dendrite Source: Ensembl
  • LUBAC complex Source: UniProtKB
  • nucleus Source: HPA
  • postsynaptic density Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell junction, Cytoplasm, Synapse

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi114V → D: Abolishes homodimerization. 1 Publication1
Mutagenesisi272I → A: Abolishes interaction with RNF31 and ability to mediate linear polyubiquitination. 1 Publication1
Mutagenesisi354C → S: Abolishes binding to ubiquitin without affecting interaction with RNF31; when associated with S-357. 1 Publication1
Mutagenesisi357C → S: Abolishes binding to ubiquitin without affecting interaction with RNF31; when associated with S-354. 1 Publication1
Mutagenesisi358 – 359TF → LV: Abolishes binding to ubiquitin and ability to mediate linear polyubiquitination. 1 Publication2
Mutagenesisi368C → S: Abolishes binding to ubiquitin without affecting interaction with RNF31; when associated with S-371. 1 Publication1
Mutagenesisi371C → S: Abolishes binding to ubiquitin without affecting interaction with RNF31; when associated with S-368. 1 Publication1

Organism-specific databases

DisGeNETi81858.
OpenTargetsiENSG00000179526.
PharmGKBiPA142670925.

Polymorphism and mutation databases

BioMutaiSHARPIN.
DMDMi74733523.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002806341 – 387SharpinAdd BLAST387

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei165PhosphoserineCombined sources1
Modified residuei312PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9H0F6.
MaxQBiQ9H0F6.
PaxDbiQ9H0F6.
PeptideAtlasiQ9H0F6.
PRIDEiQ9H0F6.

PTM databases

iPTMnetiQ9H0F6.
PhosphoSitePlusiQ9H0F6.

Expressioni

Tissue specificityi

Highly expressed in skeletal muscle and placenta and at lower levels in brain, heart, colon without mucosa, thymus, spleen, kidney, liver, small intestine, lung and peripheral blood leukocytes. Up-regulated in various tumor tissues such as kidney, liver, ovary and pancreas tumors.1 Publication

Gene expression databases

BgeeiENSG00000179526.
CleanExiHS_SHARPIN.
ExpressionAtlasiQ9H0F6. baseline and differential.
GenevisibleiQ9H0F6. HS.

Organism-specific databases

HPAiHPA044453.

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 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).4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
IKBKGQ9Y6K94EBI-3942966,EBI-81279
ITGA2P173015EBI-3942966,EBI-702960
ITGA5P086484EBI-3942966,EBI-1382311
MALT1Q9UDY82EBI-3942966,EBI-1047372
RNF31Q96EP02EBI-3942966,EBI-948111

GO - Molecular functioni

  • polyubiquitin binding Source: UniProtKB

Protein-protein interaction databases

BioGridi123608. 31 interactors.
DIPiDIP-57842N.
IntActiQ9H0F6. 21 interactors.
MINTiMINT-7034570.
STRINGi9606.ENSP00000381698.

Structurei

Secondary structure

1387
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni3 – 5Combined sources3
Beta strandi7 – 11Combined sources5
Helixi12 – 15Combined sources4
Beta strandi20 – 30Combined sources11
Helixi31 – 33Combined sources3
Beta strandi40 – 48Combined sources9
Beta strandi56 – 60Combined sources5
Beta strandi70 – 73Combined sources4
Helixi74 – 76Combined sources3
Beta strandi77 – 83Combined sources7
Beta strandi86 – 90Combined sources5
Beta strandi99 – 105Combined sources7
Helixi106 – 119Combined sources14

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4EMOX-ray2.00A/B/C/D1-127[»]
ProteinModelPortaliQ9H0F6.
SMRiQ9H0F6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini219 – 288Ubiquitin-likeAdd BLAST70

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 180Self-associationBy similarityAdd BLAST180
Regioni175 – 310Interaction with SHANK1By similarityAdd BLAST136

Domaini

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

Sequence similaritiesi

Contains 1 RanBP2-type zinc finger.PROSITE-ProRule annotation
Contains 1 ubiquitin-like domain.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri348 – 377RanBP2-typePROSITE-ProRule annotationAdd BLAST30

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IQMU. Eukaryota.
ENOG410YHH3. LUCA.
GeneTreeiENSGT00530000063620.
HOVERGENiHBG093954.
InParanoidiQ9H0F6.
OMAiCEMCSTQ.
OrthoDBiEOG091G0GY5.
PhylomeDBiQ9H0F6.
TreeFamiTF323486.

Family and domain databases

Gene3Di4.10.1060.10. 1 hit.
InterProiIPR031912. Sharpin_PH.
IPR029071. Ubiquitin-rel_dom.
IPR001876. Znf_RanBP2.
[Graphical view]
PfamiPF16764. Sharpin_PH. 1 hit.
[Graphical view]
SMARTiSM00547. ZnF_RBZ. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF90209. SSF90209. 1 hit.
PROSITEiPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: Q9H0F6-1) [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
MAPPAGGAAA AASDLGSAAV LLAVHAAVRP LGAGPDAEAQ LRRLQLSADP
60 70 80 90 100
ERPGRFRLEL LGAGPGAVNL EWPLESVSYT IRGPTQHELQ PPPGGPGTLS
110 120 130 140 150
LHFLNPQEAQ RWAVLVRGAT VEGQNGSKSN SPPALGPEAC PVSLPSPPEA
160 170 180 190 200
STLKGPPPEA DLPRSPGNLT EREELAGSLA RAIAGGDEKG AAQVAAVLAQ
210 220 230 240 250
HRVALSVQLQ EACFPPGPIR LQVTLEDAAS AASAASSAHV ALQVHPHCTV
260 270 280 290 300
AALQEQVFSE LGFPPAVQRW VIGRCLCVPE RSLASYGVRQ DGDPAFLYLL
310 320 330 340 350
SAPREAPATG PSPQHPQKMD GELGRLFPPS LGLPPGPQPA ASSLPSPLQP
360 370 380
SWSCPSCTFI NAPDRPGCEM CSTQRPCTWD PLAAAST
Length:387
Mass (Da):39,949
Last modified:March 1, 2001 - v1
Checksum:i33EE4BF66936AB60
GO
Isoform 2 (identifier: Q9H0F6-2) [UniParc]FASTAAdd to basket
Also known as: hSIPL1A

The sequence of this isoform differs from the canonical sequence as follows:
     309-326: TGPSPQHPQKMDGELGRL → QLVLSFLHLHQCPRPPWL
     327-387: Missing.

Show »
Length:326
Mass (Da):33,878
Checksum:iC92FE8845FD1EC3E
GO

Sequence cautioni

The sequence BAC11666 differs from that shown. Reason: Frameshift at position 334.Curated
The sequence BAC53797 differs from that shown. Reason: Frameshift at position 218.Curated
The sequence BAC53798 differs from that shown. Aberrant splicing.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti238A → P in AAH02688 (Ref. 6) Curated1
Sequence conflicti243Q → R in BAC11666 (PubMed:11230166).Curated1
Sequence conflicti257V → A in AAH02688 (Ref. 6) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_047799282S → T.Corresponds to variant rs11541804dbSNPEnsembl.1
Natural variantiVAR_047800294P → S.Corresponds to variant rs34674752dbSNPEnsembl.1
Natural variantiVAR_047801311P → R.Corresponds to variant rs35844464dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_023837309 – 326TGPSP…ELGRL → QLVLSFLHLHQCPRPPWL in isoform 2. 2 PublicationsAdd BLAST18
Alternative sequenceiVSP_023838327 – 387Missing in isoform 2. 2 PublicationsAdd BLAST61

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB052764 mRNA. Translation: BAC53797.1. Frameshift.
AB052765 mRNA. Translation: BAC53798.1. Sequence problems.
FJ655995 mRNA. Translation: ACN38058.1.
AL136816 mRNA. Translation: CAB66750.1.
AK075518 mRNA. Translation: BAC11666.1. Frameshift.
AC104592 Genomic DNA. No translation available.
CH471162 Genomic DNA. Translation: EAW82152.1.
CH471162 Genomic DNA. Translation: EAW82153.1.
CH471162 Genomic DNA. Translation: EAW82150.1.
CH471162 Genomic DNA. Translation: EAW82151.1.
BC002688 mRNA. Translation: AAH02688.2.
BC025244 mRNA. Translation: AAH25244.1.
BC034028 mRNA. Translation: AAH34028.1.
CCDSiCCDS43777.1. [Q9H0F6-1]
RefSeqiNP_112236.3. NM_030974.3. [Q9H0F6-1]
XP_016869377.1. XM_017013888.1. [Q9H0F6-2]
UniGeneiHs.529755.

Genome annotation databases

EnsembliENST00000359551; ENSP00000352551; ENSG00000179526. [Q9H0F6-2]
ENST00000398712; ENSP00000381698; ENSG00000179526. [Q9H0F6-1]
GeneIDi81858.
KEGGihsa:81858.
UCSCiuc003zba.4. human. [Q9H0F6-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB052764 mRNA. Translation: BAC53797.1. Frameshift.
AB052765 mRNA. Translation: BAC53798.1. Sequence problems.
FJ655995 mRNA. Translation: ACN38058.1.
AL136816 mRNA. Translation: CAB66750.1.
AK075518 mRNA. Translation: BAC11666.1. Frameshift.
AC104592 Genomic DNA. No translation available.
CH471162 Genomic DNA. Translation: EAW82152.1.
CH471162 Genomic DNA. Translation: EAW82153.1.
CH471162 Genomic DNA. Translation: EAW82150.1.
CH471162 Genomic DNA. Translation: EAW82151.1.
BC002688 mRNA. Translation: AAH02688.2.
BC025244 mRNA. Translation: AAH25244.1.
BC034028 mRNA. Translation: AAH34028.1.
CCDSiCCDS43777.1. [Q9H0F6-1]
RefSeqiNP_112236.3. NM_030974.3. [Q9H0F6-1]
XP_016869377.1. XM_017013888.1. [Q9H0F6-2]
UniGeneiHs.529755.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4EMOX-ray2.00A/B/C/D1-127[»]
ProteinModelPortaliQ9H0F6.
SMRiQ9H0F6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123608. 31 interactors.
DIPiDIP-57842N.
IntActiQ9H0F6. 21 interactors.
MINTiMINT-7034570.
STRINGi9606.ENSP00000381698.

PTM databases

iPTMnetiQ9H0F6.
PhosphoSitePlusiQ9H0F6.

Polymorphism and mutation databases

BioMutaiSHARPIN.
DMDMi74733523.

Proteomic databases

EPDiQ9H0F6.
MaxQBiQ9H0F6.
PaxDbiQ9H0F6.
PeptideAtlasiQ9H0F6.
PRIDEiQ9H0F6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000359551; ENSP00000352551; ENSG00000179526. [Q9H0F6-2]
ENST00000398712; ENSP00000381698; ENSG00000179526. [Q9H0F6-1]
GeneIDi81858.
KEGGihsa:81858.
UCSCiuc003zba.4. human. [Q9H0F6-1]

Organism-specific databases

CTDi81858.
DisGeNETi81858.
GeneCardsiSHARPIN.
H-InvDBHIX0017281.
HIX0124604.
HGNCiHGNC:25321. SHARPIN.
HPAiHPA044453.
MIMi611885. gene.
neXtProtiNX_Q9H0F6.
OpenTargetsiENSG00000179526.
PharmGKBiPA142670925.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IQMU. Eukaryota.
ENOG410YHH3. LUCA.
GeneTreeiENSGT00530000063620.
HOVERGENiHBG093954.
InParanoidiQ9H0F6.
OMAiCEMCSTQ.
OrthoDBiEOG091G0GY5.
PhylomeDBiQ9H0F6.
TreeFamiTF323486.

Enzyme and pathway databases

ReactomeiR-HSA-5357905. Regulation of TNFR1 signaling.
R-HSA-5357956. TNFR1-induced NFkappaB signaling pathway.
R-HSA-6794361. Interactions of neurexins and neuroligins at synapses.

Miscellaneous databases

GenomeRNAii81858.
PROiQ9H0F6.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000179526.
CleanExiHS_SHARPIN.
ExpressionAtlasiQ9H0F6. baseline and differential.
GenevisibleiQ9H0F6. HS.

Family and domain databases

Gene3Di4.10.1060.10. 1 hit.
InterProiIPR031912. Sharpin_PH.
IPR029071. Ubiquitin-rel_dom.
IPR001876. Znf_RanBP2.
[Graphical view]
PfamiPF16764. Sharpin_PH. 1 hit.
[Graphical view]
SMARTiSM00547. ZnF_RBZ. 1 hit.
[Graphical view]
SUPFAMiSSF54236. SSF54236. 1 hit.
SSF90209. SSF90209. 1 hit.
PROSITEiPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiSHRPN_HUMAN
AccessioniPrimary (citable) accession number: Q9H0F6
Secondary accession number(s): A6NEG3
, C0L3L2, D3DWL3, Q8IXF5, Q8IXF6, Q8N2E7, Q8TB25, Q9BUE4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 20, 2007
Last sequence update: March 1, 2001
Last modified: November 30, 2016
This is version 122 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.