B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations

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

doi:10.1073/pnas.2310727120

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B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations

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B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations

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

Proceedings of the National Academy of Sciences - PNAS, Vol.121(1), e2310727120

01/02/2024

DOI: 10.1073/pnas.2310727120

PMCID: PMC10769853

PMID: 38150499

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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.

Jordan

Mutation

Phosphorylation

Holoenzymes - genetics

Holoenzymes - metabolism

Protein Phosphatase 2 - metabolism

Details

Title: Subtitle: B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations
Creators: Cheng-Guo Wu - Biophysics Program, University of Wisconsin at Madison, Madison, WI 53706
Vijaya K Balakrishnan - McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705
Ronald A Merrill - University of Iowa, Molecular Physiology and Biophysics
Pankaj S Parihar - McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705
Kirill Konovolov - Chemistry Department, University of Wisconsin at Madison, Madison, WI 53706
Yu-Chia Chen - University of Wisconsin–Madison
Zhen Xu - University of Iowa, Medicine Administration
Hui Wei - The Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY 10027
Ramya Sundaresan - McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin at Madison, School of Medicine and Public Health, Madison, WI 53705
Qiang Cui - Boston University
Brian E Wadzinski - Department of Pharmacology, Vanderbilt University, Nashville, TN 37232
Mark R Swingle - Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688
Alla Musiyenko - Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688
Wendy K Chung - Boston Children's Hospital
Richard E Honkanen - Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL 36688
Aussie Suzuki - Molecular and Cellular Pharmacology Program, University of Wisconsin at Madison, Madison, WI 53706
Xuhui Huang - Chemistry Department, University of Wisconsin at Madison, Madison, WI 53706
Stefan Strack - University of Iowa, Iowa Neuroscience Institute
Yongna Xing - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.121(1), e2310727120
DOI: 10.1073/pnas.2310727120
PMID: 38150499
PMCID: PMC10769853
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Science
Grant note: R35 GM147525 / NIGMS NIH HHS
Language: English
Date published: 01/02/2024
Academic Unit: Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Medicine Administration
Record Identifier: 9984538958302771

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