Structural basis of the selective activation of enzyme isoforms: Allosteric response to activators of β1- and β2-containing AMPK complexes

Elnaz Aledavood; Alessia Forte; Carolina Estarellas; F Javier Luque

doi:10.1016/j.csbj.2021.05.056

Structural basis of the selective activation of enzyme isoforms: Allosteric response to activators of β1- and β2-containing AMPK complexes

Comput Struct Biotechnol J. 2021 Jun 5:19:3394-3406. doi: 10.1016/j.csbj.2021.05.056. eCollection 2021.

Authors

Elnaz Aledavood¹, Alessia Forte¹, Carolina Estarellas¹, F Javier Luque¹

Affiliation

¹ Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB) and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Av. Prat de la Riba 171, Santa Coloma de Gramenet 08921, Spain.

Abstract

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 β1- and β2-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 α2β1 complex, in contrast with a larger resilience of the α2β2 species, especially regarding modulation by A-769662. Furthermore, binding of activators to α2β1 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 β-subunit isoforms, particularly regarding the β1Asn111 → β2Asp111 substitution as a key factor in modulating the mechanical sensitivity of β1- and β2-containing AMPK complexes. Our studies pave the way for the design of activators tailored for improving the therapeutic treatment of tissue-specific metabolic disorders.

Keywords: AMPK; Allostery; Enzyme activation; Enzyme isoforms; Protein dynamics; Structure-function relationships.