Steered molecular dynamic simulations reveal Marfan syndrome mutations disrupt fibrillin-1 cbEGF domain mechanosensitive calcium binding.

ABSTRACT: Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate

SUBMITTER: Haller SJ 

PROVIDER: S-EPMC7545174 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature