Obscurin Signaling Through its Rho-GEF and PH Domains

University Of Maryland Baltimore, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Skeletal muscle is an highly organized structure composed of repeating contractile units known as sarcomeres. During embryonic development, sarcomeres are assembled and organized to form myofibrils. Defects in the proteins that form the sarcomeres and the cytoskeleton that supports the contractile apparatus can lead to muscular dystrophies. The signaling pathways that lead to gene transcription in normal development of myofibrils during embryogenesis and early postnatal life are thought to be the same as those that lead to gene transcription in physiological and pathological hypertrophic states in adult muscle. Obscurin, a recently discovered giant protein in skeletal muscle, contains a signaling domain, the Rho-GEF domain, which is likely to be involved in myofibrillogenesis. I have discovered that a Ran binding protein, RanBPM is a binding partner of the Rho-GEF domain of obscurin. I propose to determine the functional significance of the Rho-GEF domain, specifically by determining the importance of its interaction with RanBPM and examining this interaction in skeletal muscle. I will achieve this by using the yeast two hybrid assay, adenoviral transfections in vitro and in vivo, and biochemical and immunological experiments.