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Structures of the lamin A/C R335W and E347K mutants: implications for dilated cardiolaminopathies

Michela Bollati1, Alberto Barbiroli, Valentina Favalli

  • 1Dipartimento di Scienze Biomolecolari e Biotecnologie and CIMAINA, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy.

Biochemical and Biophysical Research Communications
|January 24, 2012
PubMed

Insights

Familial dilated cardiomyopathy (DCM) mutations in the Lamin AC gene, particularly in the Coil2B domain, may disrupt nuclear lamina interactions. Structural analysis of mutants R335W and E347K suggests altered protein binding as a cause of DCM.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cardiology

Background:

  • Dilated cardiomyopathy (DCM) affects myocardial function, with 25-35% of cases being familial.
  • Familial DCM often involves mutations in genes encoding cytoskeletal proteins, notably the Lamin AC gene.

Purpose of the Study:

  • To investigate the structural and functional impact of specific Lamin AC mutations associated with familial DCM.
  • To analyze the crystal structures of two Lamin AC Coil2B domain mutants, R335W and E347K.

Main Methods:

  • X-ray crystallography was used to determine the structures of Lamin AC Coil2B domain mutants.
  • Analysis focused on conserved residues R335 and E347 within the Coil2B domain.

Main Results:

  • The R335W and E347K mutations showed minimal impact on the three-dimensional structure of the Coil2B domain.
  • These mutations involve highly conserved residues crucial for protein-protein interactions.

Conclusions:

  • The structural integrity of the Coil2B domain is maintained despite these mutations.
  • Mutations likely impair Lamin A/C function by interfering with interactions with nuclear lamina components or nuclear factors.

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