| Structural highlights
Function
[UCHL5_HUMAN] Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.[1] [2] [ADRM1_HUMAN] Functions as a proteasomal ubiquitin receptor. Recruits the deubiquitinating enzyme UCHL5 at the 26S proteasome and promotes its activity.[3] [4] [5] [6] [7]
Publication Abstract from PubMed
Deubiquitinating enzymes (DUBs) control vital processes in eukaryotes by hydrolyzing ubiquitin adducts. Their activities are tightly regulated, but the mechanisms remain elusive. In particular, the DUB UCH-L5 can be either activated or inhibited by conserved regulatory proteins RPN13 and INO80G, respectively. Here we show how the DEUBAD domain in RPN13 activates UCH-L5 by positioning its C-terminal ULD domain and crossover loop to promote substrate binding and catalysis. The related DEUBAD domain in INO80G inhibits UCH-L5 by exploiting similar structural elements in UCH-L5 to promote a radically different conformation, and employs molecular mimicry to block ubiquitin docking. In this process, large conformational changes create small but highly specific interfaces that mediate activity modulation of UCH-L5 by altering the affinity for substrates. Our results establish how related domains can exploit enzyme conformational plasticity to allosterically regulate DUB activity. These allosteric sites may present novel insights for pharmaceutical intervention in DUB activity.
Mechanism of UCH-L5 Activation and Inhibition by DEUBAD Domains in RPN13 and INO80G.,Sahtoe DD, van Dijk WJ, El Oualid F, Ekkebus R, Ovaa H, Sixma TK Mol Cell. 2015 Feb 17. pii: S1097-2765(14)01017-X. doi:, 10.1016/j.molcel.2014.12.039. PMID:25702870[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yao T, Song L, Xu W, DeMartino GN, Florens L, Swanson SK, Washburn MP, Conaway RC, Conaway JW, Cohen RE. Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat Cell Biol. 2006 Sep;8(9):994-1002. Epub 2006 Aug 13. PMID:16906146 doi:ncb1460
- ↑ Yao T, Song L, Jin J, Cai Y, Takahashi H, Swanson SK, Washburn MP, Florens L, Conaway RC, Cohen RE, Conaway JW. Distinct modes of regulation of the Uch37 deubiquitinating enzyme in the proteasome and in the Ino80 chromatin-remodeling complex. Mol Cell. 2008 Sep 26;31(6):909-17. doi: 10.1016/j.molcel.2008.08.027. PMID:18922472 doi:10.1016/j.molcel.2008.08.027
- ↑ Hamazaki J, Iemura S, Natsume T, Yashiroda H, Tanaka K, Murata S. A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. EMBO J. 2006 Oct 4;25(19):4524-36. Epub 2006 Sep 21. PMID:16990800 doi:https://dx.doi.org/10.1038/sj.emboj.7601338
- ↑ Qiu XB, Ouyang SY, Li CJ, Miao S, Wang L, Goldberg AL. hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. EMBO J. 2006 Dec 13;25(24):5742-53. Epub 2006 Nov 30. PMID:17139257 doi:https://dx.doi.org/7601450
- ↑ Jorgensen JP, Lauridsen AM, Kristensen P, Dissing K, Johnsen AH, Hendil KB, Hartmann-Petersen R. Adrm1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol. 2006 Jul 28;360(5):1043-52. Epub 2006 Jun 21. PMID:16815440 doi:https://dx.doi.org/S0022-2836(06)00703-0
- ↑ Yao T, Song L, Xu W, DeMartino GN, Florens L, Swanson SK, Washburn MP, Conaway RC, Conaway JW, Cohen RE. Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat Cell Biol. 2006 Sep;8(9):994-1002. Epub 2006 Aug 13. PMID:16906146 doi:ncb1460
- ↑ Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature. 2008 May 22;453(7194):481-8. PMID:18497817 doi:10.1038/nature06926
- ↑ Sahtoe DD, van Dijk WJ, El Oualid F, Ekkebus R, Ovaa H, Sixma TK. Mechanism of UCH-L5 Activation and Inhibition by DEUBAD Domains in RPN13 and INO80G. Mol Cell. 2015 Feb 17. pii: S1097-2765(14)01017-X. doi:, 10.1016/j.molcel.2014.12.039. PMID:25702870 doi:https://dx.doi.org/10.1016/j.molcel.2014.12.039
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