| Structural highlights
Function
ADRM1_HUMAN Functions as a proteasomal ubiquitin receptor. Recruits the deubiquitinating enzyme UCHL5 at the 26S proteasome and promotes its activity.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Proteasome-ubiquitin receptor hRpn13/Adrm1 binds and activates deubiquitinating enzyme Uch37/UCHL5 and is targeted by bis-benzylidine piperidone RA190, which restricts cancer growth in mice xenografts. Here, we solve the structure of hRpn13 with a segment of hRpn2 that serves as its proteasome docking site; a proline-rich C-terminal hRpn2 extension stretches across a narrow canyon of the ubiquitin-binding hRpn13 Pru domain blocking an RA190-binding surface. Biophysical analyses in combination with cell-based assays indicate that hRpn13 binds preferentially to hRpn2 and proteasomes over RA190. hRpn13 also exists outside of proteasomes where it may be RA190 sensitive. RA190 does not affect hRpn13 interaction with Uch37, but rather directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abrogates RA190-induced accumulation of substrates at proteasomes. We propose that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains.
Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets.,Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ Nat Commun. 2017 Jun 9;8:15540. doi: 10.1038/ncomms15540. PMID:28598414[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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:http://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:http://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:http://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
- ↑ Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ. Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. Nat Commun. 2017 Jun 9;8:15540. doi: 10.1038/ncomms15540. PMID:28598414 doi:http://dx.doi.org/10.1038/ncomms15540
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