Mutated Muscle Glycoprotein Key to Understanding Muscular Dystrophy

Mutations that change the binding properties of the muscle protein dystroglycan are an underlying cause of several types of muscular dystrophy.

In skeletal muscle, the dystroglycan complex works as a transmembrane linkage between the extracellular matrix and the cytoskeleton. Alpha-dystroglycan is extracellular and binds to laminin in the basement membrane, while beta-dystroglycan is a transmembrane protein and binds to dystrophin, which is a large rod-like cytoskeletal protein. Dystrophin binds to intracellular actin cables. In this way, the dystroglycan complex, which links the extracellular matrix to the intracellular actin cables, is thought to provide structural integrity in muscle tissues. The dystroglycan complex is also known to serve as an agrin receptor in muscle, where it may regulate agrin-induced acetylcholine receptor clustering at the neuromuscular junction. There is also evidence, which suggests the function of dystroglycan as a part of the signal transduction pathway because it is shown that Grb2, a mediator of the Ras-related signal pathway, can interact with the cytoplasmic domain of dystroglycan.

Investigators at the University of Iowa (Iowa City, USA) used mass spectrometry and nuclear magnetic resonance (NMR) to conduct structural analyses of the dystroglycan complex.

They reported in the January 1, 2010, issue of the journal Science that they had identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-dystroglycan, which was required for laminin binding. Patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly had defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification was mediated by the like-acetylglucosaminyltransferase (LARGE) protein.

"Dystroglycan is a complex and unusual glycoprotein. It is heavily covered with many types of sugars. We wanted to know the shape and make up of the unique sugar chain that allows dystroglycan to bind to laminin," said senior author Dr. Kevin Campbell, professor of molecular physiology and biophysics at the University of Iowa. "This phosphate link is very unusual, which may explain why the actual structure of dystroglycan's laminin-binding sugar chain has been a mystery for many years despite the efforts of numerous research teams. The findings help explain what is happening in congenital muscular dystrophies, where the dystroglycan sugar chain is truncated and ends at the phosphate. The bare phosphate does not bind laminin; it has to be further modified."

"If we can discover the entire structure and make up of the sugar chain beyond the phosphate link, we might be able to target some of the enzymes involved in building the sugar chain, and thus, develop therapies to treat congenital muscular dystrophies," said Dr. Campbell.

Related Links:
University of Iowa