Cooperative mechanics of PR65 scaffold underlies the allosteric regulation of the phosphatase PP2A.

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dc.creatorKaynak, Burak T
dc.creatorDahmani, Zakaria L
dc.creatorDoruker, Pemra
dc.creatorBanerjee, Anupam
dc.creatorYang, Shang-Hua
dc.creatorGordon, Reuven
dc.creatorItzhaki, Laura S
dc.creatorBahar, Ivet
dc.date2024-10-30T00:30:20Z
dc.date2023-05-04
dc.date.accessioned2026-08-03T03:02:05Z
dc.descriptionPR65, a horseshoe-shaped scaffold composed of 15 HEAT (observed in Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats, forms, together with catalytic and regulatory subunits, the heterotrimeric protein phosphatase PP2A. We examined the role of PR65 in enabling PP2A enzymatic activity with computations at various levels of complexity, including hybrid approaches that combine full-atomic and elastic network models. Our study points to the high flexibility of this scaffold allowing for end-to-end distance fluctuations of 40-50 Å between compact and extended conformations. Notably, the intrinsic dynamics of PR65 facilitates complexation with the catalytic subunit and is retained in the PP2A complex enabling PR65 to engage the two domains of the catalytic subunit and provide the mechanical framework for enzymatic activity, with support from the regulatory subunit. In particular, the intra-repeat coils at the C-terminal arm play an important role in allosterically mediating the collective dynamics of PP2A, pointing to target sites for modulating PR65 function.
dc.formatPrint-Electronic
dc.formatapplication/pdf
dc.identifier0969-2126
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/375401
dc.identifier1878-4186
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/171949
dc.languageeng
dc.publisherElsevier
dc.publisherDepartment of Pharmacology
dc.publisherhttps://doi.org/10.1016/j.str.2023.02.012
dc.rightsAttribution 4.0 International
dc.rightshttps://creativecommons.org/licenses/by/4.0/
dc.subjectPP2A
dc.subjectPR65
dc.subjectallostery
dc.subjectcollective dynamics
dc.subjectconformational mechanics
dc.subjectelastic network models
dc.subjecthybrid simulations
dc.subjectrepeat protein
dc.subjectProtein Phosphatase 2
dc.subjectAllosteric Regulation
dc.subjectProtein Binding
dc.subjectCatalytic Domain
dc.titleCooperative mechanics of PR65 scaffold underlies the allosteric regulation of the phosphatase PP2A.
dc.typeArticle

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