Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme

Cheng-Guo Wu; Vijaya K Balakrishnan; Pankaj S Parihar; Kirill Konovolov; Yu-Chia Chen; Ronald A Merrill; Hui Wei; Bridget Carragher; Ramya Sundaresan; Qiang Cui; Brian E Wadzinski; Mark R Swingle; Alla Musiyenko; Richard Honkanen; Wendy K Chung; Aussie Suzuki; Stefan Strack; Xuhui Huang; Yongna Xing

doi:10.1101/2023.03.09.530109

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Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme

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Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme

Cheng-Guo Wu, Vijaya K Balakrishnan, Pankaj S Parihar, Kirill Konovolov, Yu-Chia Chen, Ronald A Merrill, Hui Wei, Bridget Carragher, Ramya Sundaresan, Qiang Cui, …

bioRxiv : the preprint server for biology

04/05/2023

DOI: 10.1101/2023.03.09.530109

PMCID: PMC10103954

PMID: 37066309

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https://doi.org/10.1101/2023.03.09.530109View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

An increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrent missense mutations have been discovered in B56δ (encoded by ), 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.

Details

Title: Subtitle: Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme
Creators: Cheng-Guo Wu
Vijaya K Balakrishnan
Pankaj S Parihar
Kirill Konovolov
Yu-Chia Chen
Ronald A Merrill
Hui Wei
Bridget Carragher
Ramya Sundaresan
Qiang Cui
Brian E Wadzinski
Mark R Swingle
Alla Musiyenko
Richard Honkanen
Wendy K Chung
Aussie Suzuki
Stefan Strack
Xuhui Huang
Yongna Xing
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2023.03.09.530109
PMID: 37066309
PMCID: PMC10103954
Language: English
Date posted: 04/05/2023
Academic Unit: Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984398210202771

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