Abstract
Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD). It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy.
Highlights
The stability of muscle cells depends on the ability of cytoskeletal proteins to dynamically resist the mechanical shear stresses which occur during muscle activity
Through the combination of homology modeling and the comparison of surface properties and molecular dynamics simulations, we have proposed a molecular description of the whole dystrophin central rod domain
In conclusion, our computational analysis clearly establishes that dystrophin repeats are highly diverse, with electrostatic and hydrophobic surfaces that are far from identical
Summary
The stability of muscle cells depends on the ability of cytoskeletal proteins to dynamically resist the mechanical shear stresses which occur during muscle activity. Dystrophin is one of these skeletal muscle cytoskeletal proteins [1,2] and is part of the large dystrophin-glycoprotein sarcolemmal complex [3,4]. The current hypothesis is that dystrophin protects muscle cell membranes from rupture [6]. After a first hinge is the large central rod domain (#2), composed of 24 spectrinlike repeats interrupted by two more hinges. This domain interacts with membrane phospholipids and with a number of cytosolic proteins such as filamentous actin (F-actin), n-nitric oxide synthase (nNOS) and microtubules. There is the cysteinerich domain (#3), which anchors dystrophin to the intrinsic membrane protein b-dystroglycan.
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