Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics

Àlex L. González, Daniel Fernández-Remacha, José Ignacio Borrell, Jordi Teixidó, Roger Estrada-Tejedor

Research output: Indexed journal article Articlepeer-review

Abstract

The muscleblind-like protein family (MBNL) plays a prominent role in the regulation of alternative splicing. Consequently, the loss of MBNL function resulting from sequestration by RNA hairpins triggers the development of a neuromuscular disease called myotonic dystrophy (DM). Despite the sequence and structural similarities between the four zinc-finger domains that form MBNL1, recent studies have revealed that the four binding domains have differentiated splicing activity. The dynamic behaviors of MBNL1 ZnFs were simulated using conventional molecular dynamics (cMD) and steered molecular dynamics (sMD) simulations of a structural model of MBNL1 protein to provide insights into the binding selectivity of the four zinc-finger (ZnF) domains toward the GpC steps in YGCY RNA sequence. In accordance with previous studies, our results suggest that both global and local residue fluctuations on each domain have great impacts on triggering alternative splicing, indicating that local motions in RNA-binding domains could modulate their affinity and specificity. In addition, all four ZnF domains provide a distinct RNA-binding environment in terms of structural sampling and mobility that may be involved in the differentiated MBNL1 splicing events reported in the literature.

Original languageEnglish
Article number16147
JournalInternational Journal of Molecular Sciences
Volume23
Issue number24
DOIs
Publication statusPublished - Dec 2022

Keywords

  • MBNL1
  • molecular dynamics
  • myotonic dystrophy

Fingerprint

Dive into the research topics of 'Cognate RNA-Binding Modes by the Alternative-Splicing Regulator MBNL1 Inferred from Molecular Dynamics'. Together they form a unique fingerprint.

Cite this