Cryo-EM structures of the human PA200 and PA200-20S complex reveal regulation of proteasome gate opening and two PA200 apertures

PLoS Biology
Hongxin GuanSongying Ouyang

Abstract

Proteasomes are highly abundant and conserved protease complexes that eliminate unwanted proteins in the cells. As a single-chain ATP-independent nuclear proteasome activator, proteasome activator 200 (PA200) associates with 20S core particle to form proteasome complex that catalyzes polyubiquitin-independent degradation of acetylated histones, thus playing a pivotal role in DNA repair and spermatogenesis. Here, we present cryo-electron microscopy (cryo-EM) structures of the human PA200-20S complex and PA200 at 2.72 Å and 3.75 Å, respectively. PA200 exhibits a dome-like architecture that caps 20S and uses its C-terminal YYA (Tyr-Tyr-Ala) to induce the α-ring rearrangements and partial opening of the 20S gate. Our structural data also indicate that PA200 has two openings formed by numerous positively charged residues that respectively bind (5,6)-bisdiphosphoinositol tetrakisphosphate (5,6[PP]2-InsP4) and inositol hexakisphosphate (InsP6) and are likely to be the gates that lead unfolded proteins through PA200 and into the 20S. Besides, our structural analysis of PA200 found that the bromodomain (BRD)-like (BRDL) domain of PA200 shows considerable sequence variation in comparison to other human BRDs, as it contains only 82 residu...Continue Reading

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Citations

Oct 10, 2020·Journal of Cell Science·Richard S MarshallRichard D Vierstra
Dec 10, 2020·Polymers·Lucia Račková, Erika Csekes
Feb 11, 2021·International Journal of Molecular Sciences·Abdennour DouidaKrisztina Tar
Nov 4, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Saimai ChatreeIvana Vucenik
Feb 28, 2021·The Journal of Biological Chemistry·Alicia BurrisJeroen Roelofs
Apr 28, 2021·Cell Chemical Biology·Fulya TürkerSeth S Margolis

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Methods Mentioned

BETA
acetylation
gel filtration
transmission electron microscopy
chip
Fluorescence

Software Mentioned

PyMOL Molecular Graphics System
cisTEM
SerialEM
Gautomatch
space
EXCEL
PyMOL
real
Coot
Chimera

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