Reviewed, UniProtKB/Swiss-Prot Q8C863 (ITCH_MOUSE)

Names and origin

Protein names

Recommended name:
    E3 ubiquitin-protein ligase Itchy
    EC=6.3.2.-

Gene names

Name:

Itch

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	864 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteosomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B By similarity. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts via its WW domains with OCLN, NOTCH1, JUN and JUNB. Interacts with DRPLA and NFE2. Interacts with ARHGEF7 By similarity. Interacts with NDFIP1 in vitro. Interacts with RNF11 By similarity.
Subcellular location	Cytoplasm. Nucleus.
Tissue specificity	Widely expressed.
Post-translational modification	Phosphorylated on tyrosine residues By similarity.
Involvement in disease	Defects in Itch are the cause of the itchy phenotype which is an inflammatory and immunological condition characterized by inflammation in the lung and stomach, hyperplasia in lymphoid and hematopoietic cells and constant itching in the skin. Ref.1
Sequence similarities	Contains 1 C2 domain. Contains 1 HECT (E6AP-type E3 ubiquitin-protein ligase) domain. Contains 4 WW domains.
Caution	It is uncertain whether Met-1 or Met-11 is the initiator.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Repeat
Molecular function	Ligase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	negative regulation of alpha-beta T cell proliferation Inferred from mutant phenotype. Source: MGI positive regulation of T cell anergy Inferred from mutant phenotype. Source: MGI positive regulation of protein catabolic process Inferred from direct assay. Source: MGI protein polyubiquitination Inferred from direct assay. Source: MGI protein ubiquitination during ubiquitin-dependent protein catabolic process Inferred from direct assay. Source: MGI
Cellular component	cell cortex Inferred from direct assay. Source: MGI cytoplasmic vesicle Inferred from direct assay. Source: MGI membrane fraction Inferred from direct assay. Source: MGI nucleus Inferred from direct assay. Source: MGI
Molecular function	acid-amino acid ligase activity Inferred from electronic annotation. Source: InterPro protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Cflar	O35732-1	1	EBI-851782,EBI-851729

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q8C863-1)

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.

Note: Major form.

Isoform 2 (identifier: Q8C863-2)

The sequence of this isoform differs from the canonical sequence as follows:
     742-759: LLCGMQEIDLNDWQRHAI → MNFYLLKHTSKYSFRYLF
     760-864: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 864

864

E3 ubiquitin-protein ligase Itchy

PRO_0000120318

Regions

Domain

5 – 99

95

C2

Domain

287 – 320

34

WW 1

Domain

319 – 352

34

WW 2

Domain

399 – 432

34

WW 3

Domain

439 – 472

34

WW 4

Domain

530 – 864

335

HECT

Compositional bias

218 – 223

6

Poly-Pro

Sites

Active site

832

1

Glycyl thioester intermediate By similarity

Amino acid modifications

Modified residue

304

1

Phosphotyrosine By similarity

Modified residue

381

1

Phosphotyrosine By similarity

Natural variations

Alternative sequence

742 – 759

18

LLCGM…QRHAI → MNFYLLKHTSKYSFRYLF in isoform 2.

VSP_008452

Alternative sequence

760 – 864

105

Missing in isoform 2.

VSP_008453

Experimental info

Mutagenesis

832

1

C → A: Loss of ubiquitin protein ligase activity. Ref.6

Secondary structure

1

.

.

.

.

.

.

.

.

.

864

Helix Strand Turn

Details...

Beta strand

407 – 409

3

Beta strand

411 – 413

3

Beta strand

415 – 419

5

Turn

420 – 423

4

Beta strand

424 – 426

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 3, 2003. Version 2. Checksum: 905FDBE00A1EA7EA	FASTA	864	98,994
	10 20 30 40 50 60 MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 70 80 90 100 110 120 NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL 130 140 150 160 170 180 QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS 190 200 210 220 230 240 EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD 250 260 270 280 290 300 GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH 310 320 330 340 350 360 GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ 370 380 390 400 410 420 WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH 430 440 450 460 470 480 NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG 490 500 510 520 530 540 PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV 550 560 570 580 590 600 IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR 610 620 630 640 650 660 FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC 670 680 690 700 710 720 GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE 730 740 750 760 770 780 GFNEILPQQY LQYFDAKELE VLLCGMQEID LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI 790 800 810 820 830 840 DNEKRMRLLQ FVTGTCRLPV GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP 850 860 YKSYEQLKEK LLFAIEETEG FGQE
	Isoform 2. Checksum: B1820795111F666B	FASTA	759	86,702
	10 20 30 40 50 60 MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT 70 80 90 100 110 120 NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL 130 140 150 160 170 180 QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS 190 200 210 220 230 240 EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD 250 260 270 280 290 300 GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH 310 320 330 340 350 360 GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ 370 380 390 400 410 420 WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH 430 440 450 460 470 480 NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG 490 500 510 520 530 540 PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV 550 560 570 580 590 600 IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR 610 620 630 640 650 660 FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC 670 680 690 700 710 720 GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE 730 740 750 GFNEILPQQY LQYFDAKELE VMNFYLLKHT SKYSFRYLF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice." Perry W.L., Hustad C.M., Swing D.A., O'Sullivan T.N., Jenkins N.A., Copeland N.G. Nat. Genet. 18:143-146(1998) [PubMed: 9462742] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DISEASE. Strain: C3H/HeJ. Tissue: Kidney.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Strain: C57BL/6J. Tissue: Head.
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: C57BL/6. Tissue: Brain.
[4]	"N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein." Harvey K.F., Shearwin-Whyatt L.M., Fotia A., Parton R.G., Kumar S. J. Biol. Chem. 277:9307-9317(2002) [PubMed: 11748237] [Abstract] Cited for: INTERACTION WITH NDFIP1.
[5]	"Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation." Fang D., Elly C., Gao B., Fang N., Altman Y., Joazeiro C., Hunter T., Copeland N.G., Jenkins N.A., Liu Y.C. Nat. Immunol. 3:281-287(2002) [PubMed: 11828324] [Abstract] Cited for: FUNCTION, INTERACTION WITH JUN AND JUNB.
[6]	"Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase." Qiu L., Joazeiro C., Fang N., Wang H.-Y., Elly C., Altman Y., Fang D., Hunter T., Liu Y.-C. J. Biol. Chem. 275:35734-35737(2000) [PubMed: 10940313] [Abstract] Cited for: INTERACTION WITH NOTCH1, MUTAGENESIS OF CYS-832.
[7]	"The tight junction-specific protein occludin is a functional target of the E3 ubiquitin-protein ligase itch." Traweger A., Fang D., Liu Y.-C., Stelzhammer W., Krizbai I.A., Fresser F., Bauer H.-C., Bauer H. J. Biol. Chem. 277:10201-10208(2002) [PubMed: 11782481] [Abstract] Cited for: INTERACTION WITH OCNL.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

AF037454 mRNA. Translation: AAB99764.1. Different initiation.
AK048303 mRNA. Translation: BAC33298.1.
BC062934 mRNA. Translation: AAH62934.1.

IPI

IPI00380162.
IPI00380163.

RefSeq

NP_032421.2.

UniGene

Mm.208286
Mm.462050

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1YIU	NMR	-	A	399-432	[»]
2JO9	NMR	-	A	399-432	[»]
2JOC	NMR	-	A	399-432	[»]

SMR

Q8C863. Positions 13-145.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q8C863. 2 interactions.

STRING

Q8C863.

PTM databases

PhosphoSite

Q8C863.

Proteomic databases

PRIDE

Q8C863.

Genome annotation databases

Ensembl

ENSMUST00000029126; ENSMUSP00000029126; ENSMUSG00000027598; Mus musculus. [Genome view]
ENSMUST00000109685; ENSMUSP00000105307; ENSMUSG00000027598; Mus musculus. [Genome view]

GeneID

16396.

KEGG

mmu:16396.

UCSC

uc008nkd.1. mouse.
uc008nke.1. mouse.

Organism-specific databases

CTD

16396.

MGI

MGI:1202301. Itch.

Phylogenomic databases

HOVERGEN

Q8C863.

OMA

NSNTSEG

OrthoDB

EOG9RBT45

Gene expression databases

ArrayExpress

Q8C863.

Bgee

Q8C863.

CleanEx

MM_ITCH.

Genevestigator

Q8C863.

GermOnline

ENSMUSG00000027598. Mus musculus.

Family and domain databases

InterPro

IPR000008. C2_Ca-dep.
IPR008973. C2_Ca/lipid-bd_reg_CaLB.
IPR018029. C2_membr_targeting.
IPR000569. HECT.
IPR001202. WW_Rsp5_WWP.
[Graphical view]

Pfam

PF00168. C2. 1 hit.
PF00632. HECT. 1 hit.
PF00397. WW. 4 hits.
[Graphical view]

SMART

SM00239. C2. 1 hit.
SM00119. HECTc. 1 hit.
SM00456. WW. 4 hits.
[Graphical view]

PROSITE

PS50004. C2. 1 hit.
PS50237. HECT. 1 hit.
PS01159. WW_DOMAIN_1. 4 hits.
PS50020. WW_DOMAIN_2. 4 hits.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

289541.

SOURCE

Search...

Entry information

Entry name

ITCH_MOUSE

Accession

Primary (citable) accession number: Q8C863
Secondary accession number(s): O54971

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 3, 2003
Last sequence update:	October 3, 2003
Last modified:	November 24, 2009
This is version 74 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)