5 years ago

Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle

Conformational Landscape of the p28-Bound Human Proteasome Regulatory Particle
The proteasome holoenzyme is activated by its regulatory particle (RP) consisting of two subcomplexes, the lid and the base. A key event in base assembly is the formation of a heterohexameric ring of AAA-ATPases, which is guided by at least four RP assembly chaperones in mammals: PAAF1, p28/gankyrin, p27/PSMD9, and S5b. Using cryogenic electron microscopy, we analyzed the non-AAA structure of the p28-bound human RP at 4.5 Å resolution and determined seven distinct conformations of the Rpn1-p28-AAA subcomplex within the p28-bound RP at subnanometer resolutions. Remarkably, the p28-bound AAA ring does not form a channel in the free RP and spontaneously samples multiple “open” and “closed” topologies at the Rpt2-Rpt6 and Rpt3-Rpt4 interfaces. Our analysis suggests that p28 assists the proteolytic core particle to select a specific conformation of the ATPase ring for RP engagement and is released in a shoehorn-like fashion in the last step of the chaperone-mediated proteasome assembly.

Graphical abstract



At least four chaperones guide the assembly of the proteasome regulatory particle. Lu, Wu, et al. present the cryo-EM structures and dynamics of the p28 chaperone bound to the human proteasome regulatory particle and reveal how it guides conformational selection upon association of the regulatory and core particles.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304094

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