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Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A.

Title: Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A.
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Name(s): Guo, Cong, author
Zhou, Huan-Xiang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-11-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The holoenzyme complex of protein kinase A is in an inactive state; activation involves ordered cAMP binding to two tandem domains of the regulatory subunit and release of the catalytic subunit. Deactivation has been less studied, during which the two cAMPs unbind from the regulatory subunit to allow association of the catalytic subunit to reform the holoenzyme complex. Unbinding of the cAMPs appears ordered as indicated by a large difference in unbinding rates from the two sites, but the cause has remained elusive given the structural similarity of the two tandem domains. Even more intriguingly, NMR data show that allosteric communication between the two domains is unidirectional. Here, we present a mechanism for the unidirectionality, developed from extensive molecular dynamics simulations of the tandem domains in different cAMP-bound forms. Disparate responses to cAMP releases from the two sites (A and B) in conformational flexibility and chemical shift perturbation confirmed unidirectional allosteric communication. Community analysis revealed that the A-site cAMP, by forming across-domain interactions, bridges an essential pathway for interdomain communication. The pathway is impaired when this cAMP is removed but remains intact when only the B-site cAMP is removed. Specifically, removal of the A-site cAMP leads to the separation of the two domains, creating room for binding the catalytic subunit. Moreover, the A-site cAMP, by maintaining interdomain coupling, retards the unbinding of the B-site cAMP and stalls an unproductive pathway of cAMP release. Our work expands the perspective on allostery and implicates functional importance for the directionality of allostery.
Identifier: FSU_pmch_27791125 (IID), 10.1073/pnas.1610142113 (DOI), PMC5098638 (PMCID), 27791125 (RID), 27791125 (EID), 1610142113 (PII)
Keywords: NMR spectroscopy, CAMP, Community analysis, Molecular dynamics, Unidirectional allostery
Grant Number: R01 GM058187, R35 GM118091
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098638.
Subject(s): Allosteric Regulation/physiology
Amino Acid Sequence
Binding Sites
Catalytic Domain
Cyclic AMP/metabolism
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/chemistry
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/metabolism
Cyclic AMP-Dependent Protein Kinases/chemistry
Cyclic AMP-Dependent Protein Kinases/genetics
Cyclic AMP-Dependent Protein Kinases/metabolism
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Dynamics Simulation
Mutation
Protein Structure, Secondary
Protein Structure, Tertiary
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_27791125
Owner Institution: FSU
Is Part Of: Proceedings of the National Academy of Sciences of the United States of America.
1091-6490
Issue: iss. 44, vol. 113

Choose the citation style.
Guo, C., & Zhou, H. -X. (2016). Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A. Proceedings Of The National Academy Of Sciences Of The United States Of America. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_27791125