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Structural Analyses of a Constitutively Active Mutant of Exchange Protein Directly Activated by cAMP

Year: 2012

Type: article

Abstract: Exchange proteins directly activated by cAMP (EPACs) are important allosteric regulators of cAMP-mediated signal transduction pathways. To understand the molecular mechanism of EPAC activation, we have combined site-directed mutagenesis, X-ray crystallography, and peptide amide hydrogen/deuterium exchange mass spectrometry (DXMS) to probe the structural and conformational dynamics of EPAC2-F435G, a constitutively active EPAC2 mutant. Our study demonstrates that conformational dynamics plays a critical role in cAMP-induced EPAC activation. A glycine mutation at 435 position shifts the equilibrium of conformational dynamics towards the extended active conformation.

Source: PLoS ONE

DOI: 10.1371/journal.pone.0049932

Authors: Mark A. White, Sheng Li, Tamara Tsalkova, Fang C. Mei, Tong Liu, Virgil L. Woods, Xiaodong Cheng

Institutions: The University of Texas Medical Branch at Galveston, University of California San Diego, Université de Sherbrooke

Language: English

Topic: Protein Kinase Regulation and GTPase Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $2,382

Funders: National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Research Resources

Awards: Cellular Response Mechanisms to Environmental Challenge, Action of Lipolytic Enzymes, Regulation, signaling, and dynamics of glucan phosphatases, Sensitive Deuterium Exchange MS for Membrane Proteins, G1953105538, DESIGN OF AMPHIPHILIC PEPTOID ASSEMBLIES, G3119154873, STRUCTURE DRIVEN ANALYSIS OF EBOLA VIRUS RECEPTOR BINDING SITE, Current Generation Integrated Instrumentation for H-D Exchange LC-MS, G6441108465, Epac/cAMP-GEF, A Novel Intracellular cAMP Receptor, G7197482230, G7238410919, G7336788336, G7489612715, G831696663

OpenAlex ID: W1979957714

FWCI: 0.385

Cites: 31

Cited by: 12

Related to: 10