THE N-TERMINAL HALF OF DYSTROPHIN IS PROTECTED FROM PROTEOLYSIS IN-SITU

Using a panel of ''exon-specific'' monoclonal antibodies, we have exam ined the products of degradation of dystrophin by endogenous proteases in post-mortem human muscle. Four main sites of dystrophin digestion were identified, all of them in the C-terminal half of the molecule. T wo of them correspond to ''hinges'' in the central rod region and a th ird in the C-terminal domain follows the dystroglycan binding site. Th e results support the Koenig and Kunkel model for the tertiary structu re of dystrophin (J. Biol. Chem. 265 (1990) 4560-4566), but suggest th at much of the N-terminal half of dystrophin is protected from proteol ysis, possibly by interaction with the sub-sarcolemmal cytoskeleton. A lthough the results seem inconsistent with an anti-parallel dimer mode l of dystrophin in which hinge 2 and hinge 3 are close together, possi ble ways of reconciling them with such a model are also considered. (C ) 1995 Academic Press, Inc.