Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome

Yuan Shi, Xiang Chen, Suzanne Elsasser, Bradley B. Stocks, Geng Tian, Byung Hoon Lee, Yanhong Shi, Naixia Zhang, Stefanie A.H. De Poot, Fabian Tuebing, Shuangwu Sun, Jacob Vannoy, Sergey G. Tarasov, John R. Engen, Daniel Finley, Kylie J. Walters

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223 Scopus citations

Abstract

Hundreds of pathways for degradation converge at ubiquitin recognition by a proteasome. Here, we found that the five known proteasomal ubiquitin receptors in yeast are collectively nonessential for ubiquitin recognition and identified a sixth receptor, Rpn1. A site (T1) in the Rpn1 toroid recognized ubiquitin and ubiquitin-like (UBL) domains of substrate shuttling factors. T1 structures with monoubiquitin or lysine 48 diubiquitin show three neighboring outer helices engaging two ubiquitins. T1 contributes a distinct substrate-binding pathway with preference for lysine 48â€"linked chains. Proximal to T1 within the Rpn1 toroid is a second UBL-binding site (T2) that assists in ubiquitin chain disassembly, by binding the UBL of deubiquitinating enzyme Ubp6. Thus, a two-site recognition domain intrinsic to the proteasome uses distinct ubiquitin-fold ligands to assemble substrates, shuttling factors, and a deubiquitinating enzyme.

Original languageEnglish
Article numberaad9421
JournalScience
Volume351
Issue number6275
DOIs
StatePublished - 19 Feb 2016

Bibliographical note

Funding Information:
For advice, assistance, or comments on the manuscript, we thank D. Chandler-Militello, M. Gill, J. Hanna, A. Kajava, R. King, Y. Lu, Y. Li, M. Pahre, and J. Roelofs. For gifts of reagents we thank D. Clarke, M. Glickman, F. He, Y. Ye, D. Komander, C. Larsen, J. Li, U. Nowicka, S. Sadis, and W. Tansey. This research was funded by grants from the National Institutes of Health (R37-GM043601 to D.F., CA136472 to K.J.W., and R01-GM101135 to J.R.E.), by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research to K.J.W., and by a research collaboration with the Waters Corporation (J.R.E). Atomic coordinates for the Rpn1 T1 site, Rpn1 T1:ubiquitin, and Rpn1 T1: K48 diubiquitin are available through the Protein Data Bank with accession codes 2n3t, 2n3u, and 2n3v/2n3w, respectively.

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