[1]	NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND INVOLVEMENT IN FAMILIAL CYLINDROMATOSIS. DOI=10.1038/76006; PubMed=10835629 [NCBI, ExPASy, EBI, Israel, Japan] Bignell G.R., Brown C., Biggs P.J., Lakhani S.R., Jones C., Hansen J., Blair E., Hofmann B., Siebert R., Turner G., Evans D.G., Schrander-Stumpel C., Beemer F.A., Van Den Ouweland A., Halley D., Delpech B., Cleveland M.G., Leigh I., Leisti J., Rasmussen S., Wallace M.R., Fenske C., Banerjee P., Oiso N., Chaggar R., Merrett S., Leonard N., Huber M., Hohl D., Chapman P., Burn J., Swift S., Smith A., Ashworth A., Stratton M.R.; "Identification of the familial cylindromatosis tumor suppressor gene."; Nat. Genet. 25:160-165(2000).
[2]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). TISSUE=Brain; DOI=10.1093/dnares/5.6.355; PubMed=10048485 [NCBI, ExPASy, EBI, Israel, Japan] Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.; "Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."; DNA Res. 5:355-364(1998).
[3]	SEQUENCE REVISION. DOI=10.1093/dnares/9.3.99; PubMed=12168954 [NCBI, ExPASy, EBI, Israel, Japan] Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones."; DNA Res. 9:99-106(2002).
[4]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). TISSUE=Uterus; DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[5]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 397-956. TISSUE=Umbilical cord blood; DOI=10.1101/gr.140200; PubMed=11042152 [NCBI, ExPASy, EBI, Israel, Japan] Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.; "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells."; Genome Res. 10:1546-1560(2000).
[6]	FUNCTION, INTERACTION WITH NEMO, AND MUTAGENESIS OF CYS-601. DOI=10.1038/nature01803; PubMed=12917689 [NCBI, ExPASy, EBI, Israel, Japan] Trompouki E., Hatzivassiliou E., Tsichritzis T., Farmer H., Ashworth A., Mosialos G.; "CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members."; Nature 424:793-796(2003).
[7]	FUNCTION, INTERACTION WITH NEMO, AND MUTAGENESIS OF CYS-601. DOI=10.1038/nature01811; PubMed=12917690 [NCBI, ExPASy, EBI, Israel, Japan] Brummelkamp T.R., Nijman S.M.B., Dirac A.M.G., Bernards R.; "Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB."; Nature 424:797-801(2003).
[8]	FUNCTION, INTERACTION WITH NEMO AND TRAF2, AND MUTAGENESIS OF SER-457 AND HIS-871. DOI=10.1038/nature01802; PubMed=12917691 [NCBI, ExPASy, EBI, Israel, Japan] Kovalenko A., Chable-Bessia C., Cantarella G., Israeel A., Wallach D., Courtois G.; "The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination."; Nature 424:801-805(2003).
[9]	FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH TRIP. DOI=10.1084/jem.20031187; PubMed=14676304 [NCBI, ExPASy, EBI, Israel, Japan] Regamey A., Hohl D., Liu J.W., Roger T., Kogerman P., Toftgaard R., Huber M.; "The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor."; J. Exp. Med. 198:1959-1964(2003).
[10]	PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-399, AND MASS SPECTROMETRY. TISSUE=Epithelium; DOI=10.1016/j.cell.2006.09.026; PubMed=17081983 [NCBI, ExPASy, EBI, Israel, Japan] Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."; Cell 127:635-648(2006).
[11]	STRUCTURE BY NMR OF 125-304. RIKEN structural genomics initiative (RSGI); "Solution structure of the 1st and 2nd CAP-GLY domains in human cylindromatosis tumor suppressor CYLD."; Submitted (NOV-2004) to the PDB data bank.
[12]	INVOLVEMENT IN FAMILIAL CYLINDROMATAOSIS, AND INVOLVEMENT IN BRSS. DOI=10.1046/j.1523-1747.2002.01839.x; PubMed=12190880 [NCBI, ExPASy, EBI, Israel, Japan] Poblete Gutierrez P., Eggermann T., Hoeller D., Jugert F.K., Beermann T., Grussendorf-Conen E.-I., Zerres K., Merk H.F., Frank J.; "Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages."; J. Invest. Dermatol. 119:527-531(2002).
[13]	INVOLVEMENT IN BRSS. DOI=10.1046/j.1365-2230.2003.01344.x; PubMed=12950348 [NCBI, ExPASy, EBI, Israel, Japan] Scheinfeld N., Hu G., Gill M., Austin C., Celebi J.T.; "Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome."; Clin. Exp. Dermatol. 28:539-541(2003).
[14]	VARIANT MFT1 GLY-747, AND VARIANT BRSS GLY-747. DOI=10.1046/j.1523-1747.2003.12514.x; PubMed=14632188 [NCBI, ExPASy, EBI, Israel, Japan] Hu G., Oender M., Gill M., Aksakal B., Oeztas M., Guerer M.A., Celebi J.T.; "A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome."; J. Invest. Dermatol. 121:732-734(2003).
[15]	INVOLVEMENT IN MFT1. DOI=10.1111/j.1365-2133.2005.06960.x; PubMed=16307661 [NCBI, ExPASy, EBI, Israel, Japan] Liang Y.H., Gao M., Sun L.D., Liu L.J., Cui Y., Yang S., Fan X., Wang J., Xiao F.L., Zhang X.J.; "Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China."; Br. J. Dermatol. 153:1213-1215(2005).
[16]	INVOLVEMENT IN BRSS. DOI=10.1111/j.0022-202X.2005.23688.x; PubMed=15854031 [NCBI, ExPASy, EBI, Israel, Japan] Bowen S., Gill M., Lee D.A., Fisher G., Geronemus R.G., Vazquez M.E., Celebi J.T.; "Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation."; J. Invest. Dermatol. 124:919-920(2005).
[17]	INVOLVEMENT IN FAMILIAL CYLINDROMATAOSIS, AND INVOLVEMENT IN MFT1. DOI=10.1111/j.1399-0004.2006.00667.x; PubMed=16922728 [NCBI, ExPASy, EBI, Israel, Japan] Young A.L., Kellermayer R., Szigeti R., Teszas A., Azmi S., Celebi J.T.; "CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes."; Clin. Genet. 70:246-249(2006).

Comments

FUNCTION: Negative regulator of TRAF2 and NF-kappa-B signaling pathway. Has deubiquitinating activity that is directed towards non-'Lys-48'-linked polyubiquitin chains. The inhibition of NF-kappa-B activation is mediated at least in part, by the deubiquitination and inactivation of TRAF2 and, to a lesser extent, TRAF6.
CATALYTIC ACTIVITY: Ubiquitin C-terminal thioester + H₂O = ubiquitin + a thiol.
SUBUNIT: Interacts with NEMO, TRAF2 and TRIP.
SUBCELLULAR LOCATION: Cytoplasm, perinuclear region.
ALTERNATIVE PRODUCTS: 2 named isoforms [FASTA] produced by alternative splicing.

Name 1

Isoform ID Q9NQC7-1

This is the isoform sequence displayed in this entry.

Name 2

Isoform ID Q9NQC7-2

Features which should be applied to build the isoform sequence: VSP_011277.
TISSUE SPECIFICITY: Detected in fetal brain, testis, and skeletal muscle, and at a lower level in adult brain, leukocytes, liver, heart, kidney, spleen, ovary and lung. Isoform 2 is found in all tissues except kidney.
DISEASE: Defects in CYLD are the cause of familial cylindromatosis [MIM:132700]; also known as Ancell-Spiegler cylindromas or turban tumor syndrome or dermal eccrine cylindromatosis. CYLD is an autosomal dominant and highly tumor type-specific disorder. The tumors (known as cylindromas because of their characteristic microscopic architecture) are believed to arise from or recapitulate the appearance of the eccrine or apocrine cells of the skin that secrete sweat and scent respectively. Cylindromas arise predominantly in hairy parts of the body with approximately 90% on the head and neck. The development of a confluent mass which may ulcerate or become infected has led to the designation "turban tumor syndrome". The skin tumors show differentiation in the direction of hair structures, hence the synonym trichoepithelioma.
DISEASE: Defects in CYLD are the cause of multiple familial trichoepithelioma type 1 (MFT1) [MIM:601606]; also known as epithelioma adenoides cysticum of Brooke (EAC) or hereditary multiple benign cystic epithelioma or Brooke-Fordyce trichoepitheliomas. MFT1 is an autosomal dominant dermatosis characterized by the presence of many skin tumors predominantly on the face. Since histologic examination shows dermal aggregates of basaloid cells with connection to or differentiation toward hair follicles, this disorder has been thought to represent a benign hamartoma of the pilosebaceous apparatus. Trichoepitheliomas can degenerate into basal cell carcinoma.
DISEASE: Defects in CYLD are the cause of Brooke-Spiegler syndrome (BRSS) [MIM:605041]. BRSS is an autosomal dominant disorder characterized by the appearance of multiple skin appendage tumors such as cylindroma, trichoepithelioma, and spiradenoma. These tumors are typically located in the head and neck region, appear in early adulthood, and gradually increase in size and number throughout life.
SIMILARITY: Belongs to the peptidase C67 family [view classification].
SIMILARITY: Contains 2 CAP-Gly domains.
SEQUENCE CAUTION:
- Sequence=AAF29029.1; Type=Frameshift; Positions=776, 808, 932;

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

AJ250014; CAB93533.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AB020656; BAA74872.2; ALT_INIT; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC012342; AAH12342.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF161542; AAF29029.1; ALT_FRAME; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

RefSeq

NP_001035814.1; -.
NP_001035877.1; -.
NP_056062.1; -.

UniGene

Hs.578973

3D structure databases

PDB

1IXD; NMR; -; A=460-550.	[ExPASy / RCSB / EBI]
1WHL; NMR; -; A=125-206.	[ExPASy / RCSB / EBI]
1WHM; NMR; -; A=228-304.	[ExPASy / RCSB / EBI]
2VHF; X-ray; 2.80 A; A/B=583-956.	[ExPASy / RCSB / EBI]

Detailed list of linked structures.

PDBsum

1IXD; -.
1WHL; -.
1WHM; -.
2VHF; -.

ModBase

Q9NQC7.

Protein family/group databases

MEROPS

C67.001; -.

PTM databases

PhosphoSite

Q9NQC7; -.

Organism-specific databases

HGNC:2584; CYLD.

CAB011713; -.

132700; phenotype. [NCBI / EBI]
601606; phenotype. [NCBI / EBI]
605018; gene. [NCBI / EBI]
605041; phenotype. [NCBI / EBI]

Orphanet

211; Cylindromatosis, familial.

PA27084; -.

Gene expression databases

ArrayExpress

Q9NQC7; -.

CleanEx

HS_CYLD; -.

GermOnline

ENSG00000083799; Homo sapiens.

Ontologies

GO:0005856;	Cellular component: cytoskeleton (non-traceable author statement from UniProtKB).
GO:0005840;	Cellular component: ribosome (inferred from electronic annotation from InterPro).
GO:0003735;	Molecular function: structural constituent of ribosome (inferred from electronic annotation from InterPro).
GO:0004221;	Molecular function: ubiquitin thiolesterase activity (non-traceable author statement from UniProtKB).
GO:0045786;	Biological process: negative regulation of cell cycle (inferred from electronic annotation from UniProtKB-KW).
GO:0006412;	Biological process: translation (inferred from electronic annotation from InterPro).
GO:0006511;	Biological process: ubiquitin-dependent protein catabolic process (non-traceable author statement from UniProtKB).
QuickGo view.

Family and domain databases

InterPro

IPR000938; Cytoskel-assoc-prot_CAP-Gly.
IPR001394; Peptidase_C19.
IPR001593; Ribosomal_S3Ae.
Graphical view of domain structure.

PANTHER

PTHR11830; Ribosomal_S3AE; 1.

Pfam

PF01302; CAP_GLY; 3.
Pfam graphical view of domain structure.

PROSITE

PS00845; CAP_GLY_1; 1.
PS50245; CAP_GLY_2; 2.
PS00972; UCH_2_1; 1.
PS00973; UCH_2_2; FALSE_NEG.
PS50235; UCH_2_3; 1.
PROSITE graphical view of domain structure (profiles).

ProtoNet

Q9NQC7.

Genome annotation databases

Ensembl

ENSG00000083799; Homo sapiens. [Contig view]

GeneID

1540; -.

KEGG

hsa:1540; -.

Phylogenomic databases

HOGENOM

Q9NQC7; -.

HOVERGEN

Q9NQC7; -.

Other

NextBio

6377; -.

SOURCE

CYLD; Homo sapiens.

UniRef

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

3D-structure; Alternative splicing; Anti-oncogene; Cell cycle; Cytoplasm; Disease mutation; Hydrolase; Phosphoprotein; Protease; Repeat; Thiol protease; Ubl conjugation pathway.

Features

Feature table viewer

Feature aligner

`Key`	`From To`	`Length`	`Description`	`FTId`
`CHAIN`	`1 956`	`956`	`Probable ubiquitin carboxyl-terminal hydrolase CYLD.`	`PRO_0000080698`
`DOMAIN`	`153 198`	`46`	`CAP-Gly 1.`
`DOMAIN`	`492 535`	`44`	`CAP-Gly 2.`
`REGION`	`106 593`	`488`	`Interaction with TRIP.`
`REGION`	`394 469`	`76`	`Interaction with TRAF2.`
`REGION`	`470 684`	`215`	`Interaction with NEMO.`
`ACT_SITE`	`601 601`		`By similarity.`
`ACT_SITE`	`871 871`		`By similarity.`
`MOD_RES`	`399 399`		`Phosphoserine.`
`VAR_SEQ`	`305 307`		`Missing (in isoform 2).`	`VSP_011277`
`VARIANT`	`747 747`	`1`	`E -> G (in MFT1 and BRSS).`	`VAR_045967`
`MUTAGEN`	`457 457`		`S->A: Abolishes binding to TRAF2.`
`MUTAGEN`	`601 601`		`C->S: Loss of deubiquitinating activity.`
`MUTAGEN`	`871 871`		`H->N: Loss of deubiquitinating activity.`
`STRAND`	`130 134`	`5`
`STRAND`	`136 139`	`4`
`STRAND`	`141 149`	`9`
`STRAND`	`154 157`	`4`
`STRAND`	`163 167`	`5`
`STRAND`	`169 171`	`3`
`TURN`	`191 193`	`3`
`STRAND`	`194 197`	`4`
`HELIX`	`199 201`	`3`
`STRAND`	`202 204`	`3`
`STRAND`	`235 240`	`6`
`STRAND`	`243 253`	`11`
`TURN`	`259 261`	`3`
`STRAND`	`264 272`	`9`
`STRAND`	`278 280`	`3`
`STRAND`	`283 285`	`3`
`STRAND`	`293 298`	`6`
`HELIX`	`299 301`	`3`
`TURN`	`463 465`	`3`
`STRAND`	`466 468`	`3`
`STRAND`	`474 478`	`5`
`STRAND`	`480 482`	`3`
`STRAND`	`486 492`	`7`
`STRAND`	`495 497`	`3`
`STRAND`	`501 508`	`8`
`STRAND`	`514 518`	`5`
`STRAND`	`531 535`	`5`
`HELIX`	`536 538`	`3`
`STRAND`	`539 541`	`3`
`HELIX`	`584 586`	`3`
`STRAND`	`588 591`	`4`
`HELIX`	`601 611`	`11`
`STRAND`	`612 614`	`3`
`HELIX`	`615 617`	`3`
`HELIX`	`618 622`	`5`
`HELIX`	`633 642`	`10`
`HELIX`	`645 650`	`6`
`STRAND`	`652 654`	`3`
`HELIX`	`656 669`	`14`
`HELIX`	`682 690`	`9`
`TURN`	`691 694`	`4`
`STRAND`	`699 704`	`6`
`STRAND`	`710 713`	`4`
`HELIX`	`730 741`	`12`
`STRAND`	`743 747`	`5`
`STRAND`	`750 755`	`6`
`STRAND`	`760 764`	`5`
`STRAND`	`773 775`	`3`
`HELIX`	`778 780`	`3`
`STRAND`	`781 784`	`4`
`TURN`	`789 791`	`3`
`HELIX`	`800 802`	`3`
`TURN`	`806 811`	`6`
`HELIX`	`818 824`	`7`
`HELIX`	`828 830`	`3`
`STRAND`	`859 868`	`10`
`STRAND`	`871 877`	`7`
`STRAND`	`879 881`	`3`
`STRAND`	`885 889`	`5`
`STRAND`	`905 908`	`4`
`HELIX`	`911 914`	`4`
`HELIX`	`920 925`	`6`
`HELIX`	`928 930`	`3`
`HELIX`	`935 940`	`6`
`STRAND`	`944 948`	`5`
`HELIX`	`950 952`	`3`

Sequence information

Length: 956 AA [This is the length of the unprocessed precursor]

Molecular weight: 107316 Da [This is the MW of the unprocessed precursor]

CRC64: 01831F9A83424631 [This is a checksum on the sequence]

        10         20         30         40         50         60 
MSSGLWSQEK VTSPYWEERI FYLLLQECSV TDKQTQKLLK VPKGSIGQYI QDRSVGHSRI 

        70         80         90        100        110        120 
PSAKGKKNQI GLKILEQPHA VLFVDEKDVV EINEKFTELL LAITNCEERF SLFKNRNRLS 

       130        140        150        160        170        180 
KGLQIDVGCP VKVQLRSGEE KFPGVVRFRG PLLAERTVSG IFFGVELLEE GRGQGFTDGV 

       190        200        210        220        230        240 
YQGKQLFQCD EDCGVFVALD KLELIEDDDT ALESDYAGPG DTMQVELPPL EINSRVSLKV 

       250        260        270        280        290        300 
GETIESGTVI FCDVLPGKES LGYFVGVDMD NPIGNWDGRF DGVQLCSFAC VESTILLHIN 

       310        320        330        340        350        360 
DIIPALSESV TQERRPPKLA FMSRGVGDKG SSSHNKPKAT GSTSDPGNRN RSELFYTLNG 

       370        380        390        400        410        420 
SSVDSQPQSK SKNTWYIDEV AEDPAKSLTE ISTDFDRSSP PLQPPPVNSL TTENRFHSLP 

       430        440        450        460        470        480 
FSLTKMPNTN GSIGHSPLSL SAQSVMEELN TAPVQESPPL AMPPGNSHGL EVGSLAEVKE 

       490        500        510        520        530        540 
NPPFYGVIRW IGQPPGLNEV LAGLELEDEC AGCTDGTFRG TRYFTCALKK ALFVKLKSCR 

       550        560        570        580        590        600 
PDSRFASLQP VSNQIERCNS LAFGGYLSEV VEENTPPKME KEGLEIMIGK KKGIQGHYNS 

       610        620        630        640        650        660 
CYLDSTLFCL FAFSSVLDTV LLRPKEKNDV EYYSETQELL RTEIVNPLRI YGYVCATKIM 

       670        680        690        700        710        720 
KLRKILEKVE AASGFTSEEK DPEEFLNILF HHILRVEPLL KIRSAGQKVQ DCYFYQIFME 

       730        740        750        760        770        780 
KNEKVGVPTI QQLLEWSFIN SNLKFAEAPS CLIIQMPRFG KDFKLFKKIF PSLELNITDL 

       790        800        810        820        830        840 
LEDTPRQCRI CGGLAMYECR ECYDDPDISA GKIKQFCKTC NTQVHLHPKR LNHKYNPVSL 

       850        860        870        880        890        900 
PKDLPDWDWR HGCIPCQNME LFAVLCIETS HYVAFVKYGK DDSAWLFFDS MADRDGGQNG 

       910        920        930        940        950 
FNIPQVTPCP EVGEYLKMSL EDLHSLDSRR IQGCARRLLC DAYMCMYQSP TMSLYK

Q9NQC7 in FASTA format

View entry in original UniProtKB/Swiss-Prot format
View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools