6gh9
USP15 catalytic domain in complex with small moleculeUSP15 catalytic domain in complex with small molecule
Structural highlights
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] Publication Abstract from PubMedUbiquitin specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor beta (TGF-beta) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on USP15's catalytic domain is currently unavailable. Here, we determined crystal structures of the USP15 catalytic core domain, revealing a canonical USP fold, including a finger, palm, and thumb region. Unlike for the structure of paralog USP4, the catalytic triad is in an inactive configuration with the catalytic cysteine ~10A apart from the catalytic histidine. This conformation is atypical, and a similar misaligned catalytic triad has so far been observed only for USP7, although USP15 and USP7 are differently regulated. Moreover, we found that the active site loops are flexible, resulting in a largely open ubiquitin tail binding channel. Comparison of the USP15 and USP4 structures points to a possible activation mechanism. Sequence differences between these two USPs mainly map to the S1' region likely to confer specificity, whereas the S1 ubiquitin-binding pocket is highly conserved. Isothermal titration calorimetry monoubiquitin and linear diubiquitin binding experiments showed significant differences in their thermodynamic profiles, with USP15 displaying a lower affinity for monoubiquitin than USP4. Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone in vitro A USP15-mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1' binding site. Our results reveal first insights into USP15's catalytic domain structure, conformational changes, differences between paralogs, and small molecule interactions and establish a framework for cellular probe and inhibitor development. The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel.,Ward SJ, Gratton HE, Indrayudha P, Michavila C, Mukhopadhyay R, Maurer SK, Caulton SG, Emsley J, Dreveny I J Biol Chem. 2018 Sep 18. pii: RA118.003857. doi: 10.1074/jbc.RA118.003857. PMID:30228188[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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