Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain

Alexandra E. Atang, Robyn T. Rebbeck, David D. Thomas, Adam W. Avery

Research output: Contribution to journalArticlepeer-review

Abstract

Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) are characterized by thickening, thinning, or stiffening, respectively, of the ventricular myocardium, resulting in diastolic or systolic dysfunction that can lead to heart failure and sudden cardiac death. Recently, variants in the ACTN2 gene, encoding the protein α-actinin-2, have been reported in HCM, DCM, and RCM patients. However, functional data supporting the pathogenicity of these variants is limited, and potential mechanisms by which these variants cause disease are largely unexplored. Currently, NIH ClinVar lists 34 ACTN2 missense variants, identified in cardiomyopathy patients, which we predict are likely to disrupt actin binding, based on their localization to specific substructures in the α-actinin-2 actin binding domain (ABD). We investigated the molecular consequences of three ABD localized, HCM-associated variants: A119T, M228T and T247 M. Using circular dichroism, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all three mutations are destabilizing, suggesting a structural disruption. Importantly, A119T decreased actin binding, and M228T and T247M cause increased actin binding. We suggest that altered actin binding underlies pathogenesis for cardiomyopathy mutations localizing to the ABD of α-actinin-2.

Original languageEnglish (US)
Pages (from-to)12-18
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume670
DOIs
StatePublished - Aug 30 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • Actin binding
  • Circular dichroism
  • Protein folding
  • Thermal denaturation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

Fingerprint

Dive into the research topics of 'Cardiomyopathy-associated variants alter the structure and function of the α-actinin-2 actin-binding domain'. Together they form a unique fingerprint.

Cite this