3ppa

Structure of the Dusp-Ubl domains of Usp15Structure of the Dusp-Ubl domains of Usp15

Structural highlights

3ppa is a 1 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 2.35Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UBP15_HUMAN Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling and NF-kappa-B pathways. Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP. Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

References

↑ Hetfeld BK, Helfrich A, Kapelari B, Scheel H, Hofmann K, Guterman A, Glickman M, Schade R, Kloetzel PM, Dubiel W. The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1. Curr Biol. 2005 Jul 12;15(13):1217-21. PMID:16005295 doi:10.1016/j.cub.2005.05.059
↑ Schweitzer K, Bozko PM, Dubiel W, Naumann M. CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J. 2007 Mar 21;26(6):1532-41. Epub 2007 Feb 22. PMID:17318178 doi:10.1038/sj.emboj.7601600
↑ Cayli S, Klug J, Chapiro J, Frohlich S, Krasteva G, Orel L, Meinhardt A. COP9 signalosome interacts ATP-dependently with p97/valosin-containing protein (VCP) and controls the ubiquitination status of proteins bound to p97/VCP. J Biol Chem. 2009 Dec 11;284(50):34944-53. Epub 2009 Oct 13. PMID:19826004 doi:M109.037952
↑ Huang X, Langelotz C, Hetfeld-Pechoc BK, Schwenk W, Dubiel W. The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. J Mol Biol. 2009 Aug 28;391(4):691-702. Epub 2009 Jul 1. PMID:19576224 doi:S0022-2836(09)00798-0
↑ Vos RM, Altreuter J, White EA, Howley PM. The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J Virol. 2009 Sep;83(17):8885-92. doi: 10.1128/JVI.00605-09. Epub 2009 Jun 24. PMID:19553310 doi:10.1128/JVI.00605-09
↑ Inui M, Manfrin A, Mamidi A, Martello G, Morsut L, Soligo S, Enzo E, Moro S, Polo S, Dupont S, Cordenonsi M, Piccolo S. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol. 2011 Sep 25;13(11):1368-75. doi: 10.1038/ncb2346. PMID:21947082 doi:10.1038/ncb2346
↑ Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, Garcia-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med. 2012 Feb 19;18(3):429-35. doi: 10.1038/nm.2619. PMID:22344298 doi:10.1038/nm.2619

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OCA

[1] Hetfeld BK, Helfrich A, Kapelari B, Scheel H, Hofmann K, Guterman A, Glickman M, Schade R, Kloetzel PM, Dubiel W. The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1. Curr Biol. 2005 Jul 12;15(13):1217-21. PMID:16005295 doi:10.1016/j.cub.2005.05.059

[2] Schweitzer K, Bozko PM, Dubiel W, Naumann M. CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J. 2007 Mar 21;26(6):1532-41. Epub 2007 Feb 22. PMID:17318178 doi:10.1038/sj.emboj.7601600

[3] Cayli S, Klug J, Chapiro J, Frohlich S, Krasteva G, Orel L, Meinhardt A. COP9 signalosome interacts ATP-dependently with p97/valosin-containing protein (VCP) and controls the ubiquitination status of proteins bound to p97/VCP. J Biol Chem. 2009 Dec 11;284(50):34944-53. Epub 2009 Oct 13. PMID:19826004 doi:M109.037952

[4] Huang X, Langelotz C, Hetfeld-Pechoc BK, Schwenk W, Dubiel W. The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. J Mol Biol. 2009 Aug 28;391(4):691-702. Epub 2009 Jul 1. PMID:19576224 doi:S0022-2836(09)00798-0

[5] Vos RM, Altreuter J, White EA, Howley PM. The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J Virol. 2009 Sep;83(17):8885-92. doi: 10.1128/JVI.00605-09. Epub 2009 Jun 24. PMID:19553310 doi:10.1128/JVI.00605-09

[6] Inui M, Manfrin A, Mamidi A, Martello G, Morsut L, Soligo S, Enzo E, Moro S, Polo S, Dupont S, Cordenonsi M, Piccolo S. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol. 2011 Sep 25;13(11):1368-75. doi: 10.1038/ncb2346. PMID:21947082 doi:10.1038/ncb2346

[7] Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, Garcia-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med. 2012 Feb 19;18(3):429-35. doi: 10.1038/nm.2619. PMID:22344298 doi:10.1038/nm.2619

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