Desmoplakin is a large (47 kD) structural protein in the desmosome, a subcellular structure that links the cytoskeleton of one myocyte to that of its neighbor. In total, the desmosome works to propagate the contractile force and allows for the synchronized, strong contractions of the human heartbeat. Desmoplakin structure consists of multiple, tandem spectrin repeat (SR) domains, with a single SH3 domain positioned on top of one of the N terminal SR domains. Recent evidence suggests that this SH3 domain may be a hot spot for disease-causing mutations. Here, we examine several specific mutations both in vitro and in silico. We find that several mutations linked to sudden infant death syndrome (SIDS) significantly perturb the SH3 domain structure and stability. Thus, these studies provide a compelling molecular mechanism of action for at least a subset of SIDS cases nationwide.

Desmoplakin mutations’ effect on structure and stability within the SH3 domain

254th National Meeting (2017)

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