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Harvard Medical School

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Mol. Cell, 2023 Aug 17;83(16):2959-2975.e7 | https://doi.org/10.1016/j.molcel.2023.07.023 Molecular mechanism for activation of the 26S proteasome by ZFAND5

Donghoon Lee,^1,8 Yanan Zhu,^2,3,4,7,8 Louis Colson,^2,8 Xiaorong Wang,⁵ Siyi Chen,² Emre Tkacik,² Lan Huang,⁵ Qi Ouyang,^3,4,6 Alfred L. Goldberg,^1,* and Ying Lu^2,9,*

¹Department of Cell Biology, Harvard Medical School, Boston, MA USA
²Department of Systems Biology, Harvard Medical School, Boston, MA USA
³Center for Quantitative Biology, Peking University, Beijing, China
⁴State Key Laboratory for Artificial Microstructures and Mesoscopic Physics, School of Physics, Peking University, Beijing, China
⁵School of Medicine, University of California Irvine, Irvine, Irvine, CA USA
⁶Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
⁷Present address: Division of Structural Biology, Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK
⁸These authors contributed equally
⁹Lead contact

^*Corresponding author: correspondence to Alfred L. Goldberg or Ying Lu

Abstract

Various hormones, kinases, and stressors (fasting, heat shock) stimulate 26S proteasome activity. To understand how its capacity to degrade ubiquitylated proteins can increase, we studied mouse ZFAND5, which promotes protein degradation during muscle atrophy. Cryo-electron microscopy showed that ZFAND5 induces large conformational changes in the 19S regulatory particle. ZFAND5’s AN1 Zn-finger domain interacts with the Rpt5 ATPase and its C terminus with Rpt1 ATPase and Rpn1, a ubiquitin-binding subunit. Upon proteasome binding, ZFAND5 widens the entrance of the substrate translocation channel, yet it associates only transiently with the proteasome. Dissociation of ZFAND5 then stimulates opening of the 20S proteasome gate. Using single-molecule microscopy, we showed that ZFAND5 binds ubiquitylated substrates, prolongs their association with proteasomes, and increases the likelihood that bound substrates undergo degradation, even though ZFAND5 dissociates before substrate deubiquitylation. These changes in proteasome conformation and reaction cycle can explain the accelerated degradation and suggest how other proteasome activators may stimulate proteolysis.

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형식Research article
게재일2023년 08월 (BRIC 등록일 2023-08-23)
연구진국외 연구진
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