The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy

Background: Dystrophin is an essential component of skeletal muscle cells. Its N-terminal domain binds to F-actin and its C terminus binds to the dyst rophin-associated glycoprotein (DAG) complex in the membrane. Dystrophin is therefore thought to serve as a link from the actin-based cytoskeleton of the muscle cell through the plasma membrane to the extracellular matrix. Pa thogenic mutations in dystrophin result in Duchenne or Becker muscular dyst rophy. Results: The crystal structure of the dystrophin actin-binding domain (ABD) has been determined art 2.6 Angstrom resolution. The structure is an antip arallel dimer of two ABDs each comprising two calponin homology domains (CH 1 and CH2) that are linked by a central alpha helix. The CH domains are bot h alpha-helical globular folds. Comparisons with the structures of utrophin and fimbrin ABDs reveal that the conformations of the individual CH domain s are very similar to those of dystrophin but that the arrangement of the t wo CH domains within the ABD is altered. The dystrophin dimer reveals a cha nge of 72 degrees in the orientation of one pair of CH1 and CH2 domains (fr om different monomers) relative to the other pair when compared with the ut rophin dimer. The dystrophin monomer is more elongated than the fimbrin ABD . Conclusions: The dystrophin ABD structure reveals a previously uncharacte rised arrangement of the CH domains within the ABD. This observation has im plications for the mechanism of actin binding by dystrophin and related pro teins. Examining the position of three pathogenic missense mutations within the structure suggests that they exert their effects through misfolding of the ABD, rather than through disruption of the binding to F-actin.