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

Alexandra E Atang1, Robyn T Rebbeck2, David D Thomas2

  • 1Department of Chemistry, Oakland University, Rochester, MI, 48309-4479, USA.

Biochemical and Biophysical Research Communications
|June 4, 2023
PubMed

Insights

Genetic variants in ACTN2 impact cardiac muscle function. This study reveals how specific mutations in α-actinin-2 alter actin binding, contributing to cardiomyopathies like hypertrophic cardiomyopathy.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Protein Biochemistry

Background:

  • Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) are myocardial diseases leading to heart failure and sudden cardiac death.
  • Variants in the ACTN2 gene, encoding α-actinin-2, are increasingly identified in cardiomyopathy patients.
  • Functional data and disease mechanisms for ACTN2 variants remain largely unexplored.

Purpose of the Study:

  • To investigate the functional consequences of three HCM-associated ACTN2 variants (A119T, M228T, T247M) located in the actin binding domain (ABD).
  • To determine if these variants affect protein structure, stability, and actin binding affinity.
  • To elucidate the potential pathogenic mechanisms linking ACTN2 variants to cardiomyopathy.

Main Methods:

  • Circular dichroism spectroscopy to assess the folded state of mutant α-actinin-2 ABD proteins.
  • Thermal denaturation studies to evaluate the stability of mutant proteins.
  • Actin binding assays to quantify the effect of variants on α-actinin-2's interaction with actin.

Main Results:

  • Mutant ABD proteins were found to be well-folded but exhibited decreased stability, indicating structural disruption.
  • The A119T variant significantly decreased actin binding affinity.
  • The M228T and T247M variants resulted in increased actin binding affinity.

Conclusions:

  • ACTN2 variants associated with cardiomyopathy can alter protein stability and actin binding.
  • Dysregulated actin binding by α-actinin-2 is a potential mechanism underlying HCM, DCM, and RCM.
  • These findings highlight the importance of the α-actinin-2 actin binding domain in cardiac function and disease.

Keywords:
Actin bindingCircular dichroismProtein foldingThermal denaturation

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