Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of zebrafish alpha-dystroglycan and comparison with the murine model

Davide Pirolli, Francesca Sciandra, Manuela Bozzi, Bruno Giardina, Andrea Brancaccio, Maria Cristina De Rosa

Research output: Contribution to journalArticle (Academic Journal)peer-review

10 Citations (Scopus)
275 Downloads (Pure)

Abstract

A missense amino acid mutation of valine to aspartic acid in 567 position of alpha-dystroglycan (DG), identified in dag1-mutated zebrafish, results in a reduced transcription and a complete absence of the protein. Lacking experimental structural data for zebrafish DG domains, the detailed mechanism for the observed mutation-induced destabilization of the DG complex and membrane damage, remained unclear. With the aim to contribute to a better clarification of the structure-function relationships featuring the DG complex, three-dimensional structural models of wild-type and mutant (V567D) C-terminal domain of alpha-DG from zebrafish were constructed by a template-based modelling approach. We then ran extensive molecular dynamics (MD) simulations to reveal the structural and dynamic properties of the C-terminal domain and to evaluate the effect of the single mutation on alpha-DG stability. A comparative study has been also carried out on our previously generated model of murine alpha-DG C-terminal domain including the I591D mutation, which is topologically equivalent to the V567D mutation found in zebrafish. Trajectories from MD simulations were analyzed in detail, revealing extensive structural disorder involving multiple beta-strands in the mutated variant of the zebrafish protein whereas local effects have been detected in the murine protein. A biochemical analysis of the murine alpha-DG mutant I591D confirmed a pronounced instability of the protein. Taken together, the computational and biochemical analysis suggest that the V567D/I591D mutation, belonging to the G beta-strand, plays a key role in inducing a destabilization of the alpha-DG C-terminal Ig-like domain that could possibly affect and propagate to the entire DG complex. The structural features herein identified may be of crucial help to understand the molecular basis of primary dystroglycanopathies.

Original languageEnglish
Article numbere103866
Number of pages13
JournalPLoS ONE
Volume9
Issue number7
DOIs
Publication statusPublished - 31 Jul 2014

Keywords

  • Amino Acid Sequence
  • Animals
  • Dystroglycans
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Mice
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Mutation, Missense
  • Protein Stability
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proteolysis
  • Zebrafish
  • Zebrafish Proteins
  • Comparative Study
  • Journal Article

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