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'''Unreleased structure'''


The entry 7owd is ON HOLD
==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.


Authors:  
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>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</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]]

Latest revision as of 15:57, 1 February 2024

Structure of CYLD CAP-Gly3 (467-552) bound to Ub; tetragonal space groupStructure of CYLD CAP-Gly3 (467-552) bound to Ub; tetragonal space group

Structural highlights

7owd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.71Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CYLD_HUMAN Defects in CYLD are the cause of familial cylindromatosis (FCYL) [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.[1] [2] 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.[3] [4] [5] 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.[6] [7] [8] [9]

Function

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).[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]

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[22]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Poblete Gutierrez P, Eggermann T, Holler D, Jugert FK, Beermann T, Grussendorf-Conen EI, Zerres K, Merk HF, 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. 2002 Aug;119(2):527-31. PMID:12190880 doi:10.1046/j.1523-1747.2002.01839.x
  2. ↑ Young AL, Kellermayer R, Szigeti R, Teszas A, Azmi S, Celebi JT. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. PMID:16922728 doi:10.1111/j.1399-0004.2006.00667.x
  3. ↑ Young AL, Kellermayer R, Szigeti R, Teszas A, Azmi S, Celebi JT. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006 Sep;70(3):246-9. PMID:16922728 doi:10.1111/j.1399-0004.2006.00667.x
  4. ↑ Hu G, Onder M, Gill M, Aksakal B, Oztas M, Gurer MA, Celebi JT. A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome. J Invest Dermatol. 2003 Oct;121(4):732-4. PMID:14632188 doi:10.1046/j.1523-1747.2003.12514.x
  5. ↑ Liang YH, Gao M, Sun LD, Liu LJ, Cui Y, Yang S, Fan X, Wang J, Xiao FL, Zhang XJ. 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. 2005 Dec;153(6):1213-5. PMID:16307661 doi:10.1111/j.1365-2133.2005.06960.x
  6. ↑ Poblete Gutierrez P, Eggermann T, Holler D, Jugert FK, Beermann T, Grussendorf-Conen EI, Zerres K, Merk HF, 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. 2002 Aug;119(2):527-31. PMID:12190880 doi:10.1046/j.1523-1747.2002.01839.x
  7. ↑ Hu G, Onder M, Gill M, Aksakal B, Oztas M, Gurer MA, Celebi JT. A novel missense mutation in CYLD in a family with Brooke-Spiegler syndrome. J Invest Dermatol. 2003 Oct;121(4):732-4. PMID:14632188 doi:10.1046/j.1523-1747.2003.12514.x
  8. ↑ Scheinfeld N, Hu G, Gill M, Austin C, Celebi JT. Identification of a recurrent mutation in the CYLD gene in Brooke-Spiegler syndrome. Clin Exp Dermatol. 2003 Sep;28(5):539-41. PMID:12950348
  9. ↑ Bowen S, Gill M, Lee DA, Fisher G, Geronemus RG, Vazquez ME, Celebi JT. Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005 May;124(5):919-20. PMID:15854031 doi:10.1111/j.0022-202X.2005.23688.x
  10. ↑ 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. 2003 Aug 14;424(6950):793-6. PMID:12917689 doi:http://dx.doi.org/10.1038/nature01803
  11. ↑ Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature. 2003 Aug 14;424(6950):797-801. PMID:12917690 doi:http://dx.doi.org/10.1038/nature01811
  12. ↑ Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003 Aug 14;424(6950):801-5. PMID:12917691 doi:http://dx.doi.org/10.1038/nature01802
  13. ↑ Regamey A, Hohl D, Liu JW, Roger T, Kogerman P, Toftgard R, Huber M. The tumor suppressor CYLD interacts with TRIP and regulates negatively nuclear factor kappaB activation by tumor necrosis factor. J Exp Med. 2003 Dec 15;198(12):1959-64. PMID:14676304 doi:10.1084/jem.20031187
  14. ↑ Reiley W, Zhang M, Wu X, Granger E, Sun SC. Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol. 2005 May;25(10):3886-95. PMID:15870263 doi:10.1128/MCB.25.10.3886-3895.2005
  15. ↑ Stegmeier F, Sowa ME, Nalepa G, Gygi SP, Harper JW, Elledge SJ. The tumor suppressor CYLD regulates entry into mitosis. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8869-74. Epub 2007 May 10. PMID:17495026 doi:10.1073/pnas.0703268104
  16. ↑ Friedman CS, O'Donnell MA, Legarda-Addison D, Ng A, Cardenas WB, Yount JS, Moran TM, Basler CF, Komuro A, Horvath CM, Xavier R, Ting AT. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep. 2008 Sep;9(9):930-6. doi: 10.1038/embor.2008.136. Epub 2008 Jul 18. PMID:18636086 doi:10.1038/embor.2008.136
  17. ↑ Gao J, Huo L, Sun X, Liu M, Li D, Dong JT, Zhou J. The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration. J Biol Chem. 2008 Apr 4;283(14):8802-9. doi: 10.1074/jbc.M708470200. Epub 2008, Jan 24. PMID:18222923 doi:10.1074/jbc.M708470200
  18. ↑ Gao J, Sun L, Huo L, Liu M, Li D, Zhou J. CYLD regulates angiogenesis by mediating vascular endothelial cell migration. Blood. 2010 May 20;115(20):4130-7. doi: 10.1182/blood-2009-10-248526. Epub 2010, Mar 1. PMID:20194890 doi:10.1182/blood-2009-10-248526
  19. ↑ Wickstrom SA, Masoumi KC, Khochbin S, Fassler R, Massoumi R. CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. EMBO J. 2010 Jan 6;29(1):131-44. doi: 10.1038/emboj.2009.317. Epub 2009 Nov 5. PMID:19893491 doi:10.1038/emboj.2009.317
  20. ↑ Tauriello DV, Haegebarth A, Kuper I, Edelmann MJ, Henraat M, Canninga-van Dijk MR, Kessler BM, Clevers H, Maurice MM. Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl. Mol Cell. 2010 Mar 12;37(5):607-19. doi: 10.1016/j.molcel.2010.01.035. PMID:20227366 doi:10.1016/j.molcel.2010.01.035
  21. ↑ Komander D, Lord CJ, Scheel H, Swift S, Hofmann K, Ashworth A, Barford D. The structure of the CYLD USP domain explains its specificity for Lys63-linked polyubiquitin and reveals a B box module. Mol Cell. 2008 Feb 29;29(4):451-64. PMID:18313383 doi:http://dx.doi.org/10.1016/j.molcel.2007.12.018
  22. ↑ 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. Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. Cell Rep. 2021 Oct 5;37(1):109777. PMID:34610306 doi:10.1016/j.celrep.2021.109777

7owd, resolution 1.71Å

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