8U89

The structure of the PP2A-B56Delta holoenzyme mutant - E197K

8U89 の概要

• エントリーDOI: 10.2210/pdb8u89/pdb
• EMDBエントリー: 42018
• 分子名称: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform, Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit delta isoform, Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform, ... (4 entities in total)
• 機能のキーワード: complex, phosphatase, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 171214.11

構造登録者

Wu, C.G.,Xing, Y. (登録日: 2023-09-16, 公開日: 2024-01-10)

主引用文献

Wu, C.G.,Balakrishnan, V.K.,Merrill, R.A.,Parihar, P.S.,Konovolov, K.,Chen, Y.C.,Xu, Z.,Wei, H.,Sundaresan, R.,Cui, Q.,Wadzinski, B.E.,Swingle, M.R.,Musiyenko, A.,Chung, W.K.,Honkanen, R.E.,Suzuki, A.,Huang, X.,Strack, S.,Xing, Y.
B56 delta long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.
Proc.Natl.Acad.Sci.USA, 121:e2310727120-e2310727120, 2024

PubMed Abstract: Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Our single-particle cryo-EM structures of the PP2A-B56δ holoenzyme reveal that the long, disordered arms at the B56δ termini fold against each other and the holoenzyme core. This architecture suppresses both the phosphatase active site and the substrate-binding protein groove, thereby stabilizing the enzyme in a closed latent form with dual autoinhibition. The resulting interface spans over 190 Å and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is coupled to an allosteric network responsive to phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations increase the holoenzyme activity and perturb the phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the normal variant.

PubMed: 38150499
DOI: 10.1073/pnas.2310727120

実験手法

ELECTRON MICROSCOPY (3.3 Å)