Homologous C2A Domains of Myoferlin and Dysferlin have Distinct Lipid Binding Specificities

Abstract

Myoferlin and dysferlin are members of the ferlin protein family, and both are known to play an essential role in membrane fusion events and membrane repair. They are homologous multi-C2 domain proteins that are highly expressed in skeletal and cardiac muscle cells, and to a lesser degree, in brain, kidney, lung, and placenta cells. These proteins share a high degree of overall sequence identity and a similar overall architecture. Despite similarities between myoferlin and dysferlin, only mutations in dysferlin have been shown to be associated with muscular dystrophies. Specifically, DYSF is the only gene in which mutations are associated with Limb Girdle Muscular Dystrophy Type 2B and Myoshi Myopathy; two phenotypes of dysferlinopathies which are an autosomal recessive subgroup of muscular dystrophies. Myoferlin mRNA and protein are upregulated in damaged myofibers, especially in Duchenne muscular dystrophy. This suggests that myoferlin plays a role in muscle repair mechanisms. To date, this mechanism is unknown. Moreover, it has been shown previously that myoferlin is unable to compensate for a lack of functional dysferlin in dysferlinopathies. These observations raise questions about the differences between myoferlin and dysferlin. Answering these questions will lead us to a better understanding of the myoferlin-associated membrane repair mechanism and its role as a protein which is expressed in many different tissue types. The first C2 domain of dysferlin, C2A, is the best studied domain of this protein. C2A serves as the Ca2+ sensor of dysferlin and it binds to lipids with high affinity in a Ca2+-dependent manner. In this study, we will assess the Ca2+ and lipid binding properties of myoferlin C2A domain, and will discuss the different structural and biophysical characteristics between the C2A domains of myoferlin and dysferlin.