View source for 7owd


==Structure of CYLD CAP-Gly3 (467-552) bound to Ub; tetragonal space group==
<StructureSection load='7owd' size='340' side='right'caption='[[7owd]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7owd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OWD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OWD FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.71&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7owd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7owd OCA], [https://pdbe.org/7owd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7owd RCSB], [https://www.ebi.ac.uk/pdbsum/7owd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7owd ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CYLD_HUMAN CYLD_HUMAN] Defects in CYLD are the cause of familial cylindromatosis (FCYL) [MIM:[https://omim.org/entry/132700 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.<ref>PMID:12190880</ref> <ref>PMID:16922728</ref>   Defects in CYLD are the cause of multiple familial trichoepithelioma type 1 (MFT1) [MIM:[https://omim.org/entry/601606 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.<ref>PMID:16922728</ref> <ref>PMID:14632188</ref> <ref>PMID:16307661</ref>   Defects in CYLD are the cause of Brooke-Spiegler syndrome (BRSS) [MIM:[https://omim.org/entry/605041 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.<ref>PMID:12190880</ref> <ref>PMID:14632188</ref> <ref>PMID:12950348</ref> <ref>PMID:15854031</ref> 
== Function ==
[https://www.uniprot.org/uniprot/CYLD_HUMAN CYLD_HUMAN] Protease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Has endodeubiquitinase activity. Plays an important role in the regulation of pathways leading to NF-kappa-B activation. Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation. Negative regulator of Wnt signaling. Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules. Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis. Required for normal cell cycle progress and normal cytokinesis. Inhibits nuclear translocation of NF-kappa-B. Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation. Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells. Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity).<ref>PMID:12917689</ref> <ref>PMID:12917690</ref> <ref>PMID:12917691</ref> <ref>PMID:14676304</ref> <ref>PMID:15870263</ref> <ref>PMID:17495026</ref> <ref>PMID:18636086</ref> <ref>PMID:18222923</ref> <ref>PMID:20194890</ref> <ref>PMID:19893491</ref> <ref>PMID:20227366</ref> <ref>PMID:18313383</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Non-degradative ubiquitin chains and phosphorylation events govern signaling responses by innate immune receptors. The deubiquitinase CYLD in complex with SPATA2 is recruited to receptor signaling complexes by the ubiquitin ligase LUBAC and regulates Met1- and Lys63-linked polyubiquitin and receptor signaling outcomes. Here, we investigate the molecular determinants of CYLD activity. We reveal that two CAP-Gly domains in CYLD are ubiquitin-binding domains and demonstrate a requirement of CAP-Gly3 for CYLD activity and regulation of immune receptor signaling. Moreover, we identify a phosphorylation switch outside of the catalytic USP domain, which activates CYLD toward Lys63-linked polyubiquitin. The phosphorylated residue Ser568 is a novel tumor necrosis factor (TNF)-regulated phosphorylation site in CYLD and works in concert with Ser418 to enable CYLD-mediated deubiquitination and immune receptor signaling. We propose that phosphorylated CYLD, together with SPATA2 and LUBAC, functions as a ubiquitin-editing complex that balances Lys63- and Met1-linked polyubiquitin at receptor signaling complexes to promote LUBAC signaling.

Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains.,Elliott PR, Leske D, Wagstaff J, Schlicher L, Berridge G, Maslen S, Timmermann F, Ma B, Fischer R, Freund SMV, Komander D, Gyrd-Hansen M Cell Rep. 2021 Oct 5;37(1):109777. doi: 10.1016/j.celrep.2021.109777. PMID:34610306<ref>PMID:34610306</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7owd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Thioesterase 3D structures|Thioesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Elliott PR]]
[[Category: Komander D]]