Title:Proteomics of the Dystrophin-glycoprotein Complex and Dystrophinopathy
Volume: 14
Issue: 8
Author(s): Ashling Holland, Steven Carberry and Kay Ohlendieck
Affiliation:
Keywords:
Dystrobrevin, dystroglycan, dystrophin, dystrophin-glycoprotein complex, muscular dystrophy, sarcoglycan, sarcospan,
syntrophin.
Abstract: The largest human gene is represented by the X-chromosomal dystrophin gene of 2.4 million bases, which encodes
for the membrane cytoskeletal protein dystrophin. The dystrophin isoform Dp427 has a subsarcolemmal location
and forms a supramolecular membrane assembly with a variety of glycoproteins. In healthy muscle fibres, dystrophin acts
as an actin-binding protein that links the cytoskeleton via the α/β-dystroglycan complex to the extracellular matrix protein
laminin. This trans-sarcolemmal complex is believed to stabilize the muscle surface and thus prevents membrane rupturing
during excitation-contraction-relaxation cycles. In the highly progressive muscle wasting disease Duchenne muscular
dystrophy, the primary deficiency in dystrophin causes a drastic reduction in dystrophin-associated glycoproteins, which
renders muscle fibres more susceptible to necrosis. Following the biochemical and cell biological characterization of the
dystrophin-glycoprotein complex, several mass spectrometry-based proteomic studies have investigated global changes in
dystrophin-deficient muscle tissues. This review briefly outlines the basic domain structure of Dp427 and the composition
of the dystrophin-associated glycoprotein complex from skeletal muscle. A detailed discussion of recent proteomic analyses
of the purified dystrophin-glycoprotein complex is included, as well as a summary of mass spectrometric surveys of
dystrophic specimens. The study of these new areas of muscle proteomics tends to improve our understanding of the normal
function of dystrophin in contractile fibres and better define the molecular mechanism of X-linked muscular dystrophy.
