| 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 substrate receptor hRpn13 is a promising anti-cancer target. By integrated in silico and biophysical screening, we identified a chemical scaffold that binds hRpn13 with non-covalent interactions that mimic the proteasome and a weak electrophile for Michael addition. hRpn13 Pru domain binds proteasomes and ubiquitin whereas its DEUBAD domain binds deubiquitinating enzyme UCHL5. NMR revealed lead compound XL5 to interdigitate into a hydrophobic pocket created by lateral movement of a Pru beta-hairpin with an exposed end for Proteolysis Targeting Chimeras (PROTACs). Implementing XL5-PROTACs as chemical probes identified a DEUBAD-lacking hRpn13 species (hRpn13(Pru)) present naturally with cell type-dependent abundance. XL5-PROTACs preferentially target hRpn13(Pru), causing its ubiquitination. Gene-editing and rescue experiments established hRpn13 requirement for XL5-PROTAC-triggered apoptosis. These data establish hRpn13 as an anti-cancer target for multiple myeloma and introduce an hRpn13-targeting scaffold that can be optimized for preclinical trials against hRpn13(Pru)-producing cancer types.
Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma.,Lu X, Sabbasani VR, Osei-Amponsa V, Evans CN, King JC, Tarasov SG, Dyba M, Das S, Chan KC, Schwieters CD, Choudhari S, Fromont C, Zhao Y, Tran B, Chen X, Matsuo H, Andresson T, Chari R, Swenson RE, Tarasova NI, Walters KJ Nat Commun. 2021 Dec 16;12(1):7318. doi: 10.1038/s41467-021-27570-4. PMID:34916494[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, Sabbasani VR, Osei-Amponsa V, Evans CN, King JC, Tarasov SG, Dyba M, Das S, Chan KC, Schwieters CD, Choudhari S, Fromont C, Zhao Y, Tran B, Chen X, Matsuo H, Andresson T, Chari R, Swenson RE, Tarasova NI, Walters KJ. Structure-guided bifunctional molecules hit a DEUBAD-lacking hRpn13 species upregulated in multiple myeloma. Nat Commun. 2021 Dec 16;12(1):7318. doi: 10.1038/s41467-021-27570-4. PMID:34916494 doi:http://dx.doi.org/10.1038/s41467-021-27570-4
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