Structural Basis Of The Selective Activation Of Enzyme Isoforms: Allosteric Response To Activators Of Beta 1- And Beta 2-Containing Ampk Complexes

COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL(2021)

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摘要
AMP-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 complexes, which exhibit notable differences in the sensitivity to allosteric activators. To shed light into the molecular determinants of the allosteric regulation of this energy sensor, we have examined the structural and dynamical properties of beta 1-and beta 2-containing AMPK complexes formed with small molecule activators A-769662 and SC4, and dissected the mechanical response leading to active-like enzyme conformations through the analysis of interaction networks between structural domains. The results reveal the mechanical sensitivity of the alpha 2 beta 1 complex, in contrast with a larger resilience of the alpha 2 beta 2 species, especially regarding modulation by A-769662. Furthermore, binding of activators to alpha 2 beta 1 consistently promotes the pre-organization of the ATP-binding site, favoring the adoption of activated states of the enzyme. These findings are discussed in light of the changes in the residue content of beta-subunit isoforms, particularly regarding the beta 1Asn111 -> beta 2Asp111 substitution as a key factor in modulating the mechanical sensitivity of beta 1- and beta 2-containing AMPK complexes. Our studies pave the way for the design of activators tailored for improving the therapeutic treatment of tissue-specific metabolic disorders. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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关键词
Enzyme isoforms, Allostery, Enzyme activation, AMPK, Structure-function relationships, Protein dynamics
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