Molecular mechanisms of GSK3β-driven modulation of ABLIM1 and titin interactions in cardiac muscle

bioRxiv [Preprint]. 2024 Dec 12:2024.12.07.627363. doi: 10.1101/2024.12.07.627363.

Abstract

The heart adapts to cardiac demand through a variety of mechanisms. Some of these adaptations include chemical modifications of myofilament proteins responsible for cell contraction. Interestingly, many of these chemical modifications, such as phosphorylation, are found in unstructured, or intrinsically disordered, regions of proteins. For these myofilament assoiciated proteins with intrinsic disorder (MAPIDs), it has been difficult to determine how their disordered regions influence the function of the intact protein or the myofilament as a whole. Given that cardiac dysfunction can be accompanied by dramatic shifts in post-translational modifications (PTMs) of myofilament proteins, assessment of these impacts in intrinsically disordered regions is important. We hypothesized that regulation of the actin-binding myofilament protein LIM protein 1, ABLIM1, through its IDRs occurs because PTMs, namely phosphorylation, alter their conformation ensembles. The change in conformations thereby toggles their availability for binding protein partners. To evaluate this hypothesis, we used molecular dynamics to simulate ABLIM1 and thereby determine its conformation ensemble before and after phosphorylation. In accordance with published phosphorylation data in GSK3β knockout models, our results indicate that local changes in the physicochemical properties of ABLIM1's IDRs via phosphorylation can influence its global ensemble properties, with the potential to impact its interaction with myofilament targets like titin. These findings provide important molecular-level insights into a mechanism of regulating cardiomyocyte contraction.

Publication types

  • Preprint