Q91WA6 (SHRPN_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	380 AA.
Sequence status	Complete.
Protein existence	Evidence 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. 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 SHANK1 By similarity. Interacts with EYA1 and EYA2. Ref.5
Subcellular location	Cytoplasm › cytosol 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 process	Ubl conjugation pathway
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Domain	Zinc-finger
Ligand	Metal-binding Zinc
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic nuclear changes Inferred from mutant phenotype PubMed 7792947. Source: MGI brain development Inferred from electronic annotation. Source: Compara 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 cascade Inferred from mutant phenotype Ref.8Ref.9. Source: UniProtKB protein homooligomerization Inferred from electronic annotation. Source: Compara 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_component	LUBAC complex Inferred from sequence or structural similarity. Source: UniProtKB cytosol Inferred from sequence or structural similarity. Source: UniProtKB postsynaptic density Inferred from electronic annotation. Source: Compara
Molecular_function	polyubiquitin binding Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Eya1	P97767	4	EBI-646097,EBI-1368503
Eya2	O08575	2	EBI-646097,EBI-986503

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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 380	380	Sharpin		PRO_0000280635
Regions
	Domain	216 – 285	70	Ubiquitin-like
	Zinc finger	342 – 371	30	RanBP2-type
	Region	1 – 177	177	Self-association By similarity
	Region	172 – 305	134	Interaction with SHANK1 By similarity
Amino acid modifications
	Modified residue	163	1	Phosphoserine By similarity
	Modified residue	307	1	Phosphoserine By similarity
Natural variations
	Alternative sequence	306 – 380	75	Missing in isoform 2.		VSP_023839
Experimental info
	Sequence conflict	131	1	P → Q in BAC53796. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: C7E4B8F40F6D8F05	FASTA	380	39,852
	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
	Isoform 2 [UniParc]. Checksum: 6428AD468FC5BEF6	FASTA	305	31,864
	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 REVSG

References

	« Hide 'large scale' referencesShow '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.
IPI	IPI00313934. IPI00830292.
RefSeq	NP_079616.2. NM_025340.2.
UniGene	Mm.41463.
3D structure databases
HSSP	HSSP built from PDB template 2CRC based on UniProtKB Q9BYM8.
ProteinModelPortal	Q91WA6.
SMR	Q91WA6. Positions 19-119, 212-299.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-49461N.
IntAct	Q91WA6. 3 interactions.
PTM databases
PhosphoSite	Q91WA6.
Proteomic databases
PaxDb	Q91WA6.
PRIDE	Q91WA6.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000023211; ENSMUSP00000023211; ENSMUSG00000022552.
GeneID	106025.
KEGG	mmu:106025.
UCSC	uc007wju.2. mouse.
Organism-specific databases
CTD	81858.
MGI	MGI:1913331. Sharpin.
Phylogenomic databases
eggNOG	NOG278522.
GeneTree	ENSGT00530000063620.
HOGENOM	HOG000095521.
HOVERGEN	HBG093954.
InParanoid	Q91WA6.
OMA	HELQPPP.
OrthoDB	EOG48SGTH.
Gene expression databases
ArrayExpress	Q91WA6.
Bgee	Q91WA6.
CleanEx	MM_SHARPIN.
Genevestigator	Q91WA6.
Family and domain databases
InterPro	IPR026168. SHARPIN. IPR001876. Znf_RanBP2. [Graphical view]
PANTHER	PTHR22770:SF11. PTHR22770:SF11. 1 hit.
Pfam	PF00641. zf-RanBP. 1 hit. [Graphical view]
SMART	SM00547. ZnF_RBZ. 1 hit. [Graphical view]
PROSITE	PS50053. UBIQUITIN_2. False negative. PS01358. ZF_RANBP2_1. 1 hit. PS50199. ZF_RANBP2_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	358020.
SOURCE	Search...

Entry information

Entry name

SHRPN_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 78 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program