Author:
Wu Cheng-Guo,Balakrishnan Vijaya K.,Parihar Pankaj S.,Konovolov Kirill,Chen Yu-Chia,Merrill Ronald A,Wei Hui,Carragher Bridget,Sundaresan Ramya,Cui Qiang,Wadzinski Brian E.,Swingle Mark R.,Musiyenko Alla,Honkanen Richard,Chung Wendy K.,Suzuki Aussie,Strack Stefan,Huang Xuhui,Xing Yongna
Abstract
AbstractAn increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrentde novomissense mutations have been discovered in B56δ (encoded byPPP2R5D), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56δ holoenzyme possesses closed latent and open active forms. In the closed form, the long, disordered arms of B56δ termini fold against each other and the holoenzyme core, establishing dual autoinhibition of the phosphatase active site and the substrate-binding protein groove. 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 close to an allosteric network responsive to activation phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations perturb the activation phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the wild variant.
Publisher
Cold Spring Harbor Laboratory