Year: 2024
Type: article
Abstract: New proteasomes are produced to accommodate increases in cellular catabolic demand and prevent the accumulation of cytotoxic proteins. Formation of the proteasomal 20S core complex relies on the function of the five chaperones PAC1-4 and POMP. Here, to understand how these chaperones facilitate proteasome assembly, we tagged the endogenous chaperones using CRISPR/Cas gene editing and examined the chaperone-bound complexes by cryo-EM. We observe an early α-ring intermediate subcomplex that is stabilized by PAC1-4, which transitions to β-ring assembly upon dissociation of PAC3/PAC4 and rearrangement of the PAC1 N-terminal tail. Completion of the β-ring and dimerization of half-proteasomes repositions critical lysine K33 to trigger cleavage of the β pro-peptides, leading to the concerted dissociation of POMP and PAC1/PAC2 to yield mature 20S proteasomes. This study reveals structural insights into critical points along the assembly pathway of the human proteasome and provides a molecular blueprint for 20S biogenesis.
Source: Nature Communications
Institution: Sanford Burnham Prebys Medical Discovery Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: U.S. Department of Health and Human Services, National Institutes of Health, Centers for Disease Control and Prevention, University of California, San Francisco, NIH Office of the Director, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: G1739390137, G493856676, G5124865619, Acquisition of a CMOS Imaging Device for the T12 at SBP, G7042313611, G9000102658, Cancer Center Support Grant (CCSG), Molecular mechanisms underlying the assembly of the human proteasome and endogenous protein complexes, ChimeraX -- Next Generation Visualization and Analysis Software for Multiscale Modeling, G905996767, G969542890
OpenAlex ID: W4402641293