The
dystroglycan complex is a membrane-spanning complex composed of two subunits, alpha- and
beta-dystroglycan.
alpha-dystroglycan is a cell surface peripheral
membrane protein which binds to the extracellular matrix (ECM), whereas
beta-dystroglycan is an
integral membrane protein which anchors
alpha-dystroglycan to the cell membrane. The
dystroglycan complex provides a tight link between the ECM and cell membrane. Dysfunction of the
dystroglycan complex has commonly been implicated in the molecular pathogenesis of severe forms of hereditary
neuromuscular diseases, including
Duchenne muscular dystrophy,
Fukuyama-type congenital muscular dystrophy and
sarcoglycanopathy (
LGMD2C, -D, -E and -F). To begin to clarify the pathway by which the dysfunction of the
dystroglycan complex could lead to muscle cell degeneration, we investigated the proteolytic processing of the
dystroglycan complex in this study. We demonstrate that (i) a 30 kDa fragment of
beta-dystroglycan is expressed in peripheral nerve, kidney, lung and smooth muscle, but not skeletal muscle, cardiac muscle or brain, and (ii) this fragment is the product of proteolytic processing of the extracellular domain of
beta-dystroglycan by the membrane-associated
matrix metalloproteinase (
MMP) activity. Importantly, furthermore, we demonstrate that this processing disintegrates the
dystroglycan complex. Our results indicate that the processing of
beta-dystroglycan by
MMP causes the disruption of the link between the ECM and cell membrane via the
dystroglycan complex, which could have profound effects on cell viability. Based on these and previously reported findings, we propose a hypothesis that this processing may play a crucial role in the molecular pathogenesis of
sarcoglycanopathy.