Grant: Operating Grant: Fall 2008 Priority Announcement (IMHA)

Agrin is a proteinn that plays a key role in neuromuscular junction (NMJ) development. It is best known for its induction of the acetylcholine receptor (AChR) clustering at the muscle cell and the induction and maintenance of the postsynaptic apparatus. Agrin is an extracellular matrix protein, which is composed of more than 22 separate domains, undergoing a number of modifications during its maturation and which is target for alternative mRNA splicing at three sites. Agrin mediates cell adhesion via its N-terminal domain (NtA) and induces the aggregation of acetylcholine receptor (AchR) on the postsynaptic membranes of muscle cells via its C-terminal domains (LG1-3). Disorders involving agrin lead, in Western countries, to much suffering, and also expensive therapeutic costs associated with diseases such as muscular dystrophy. Disruption of the linkage between agrin and the basement membrane in the muscular dystrophy (MDC1A) can cause extensive muscle degeneration and impairment of nerve conduction. To improve this situation, basic as well as applied research in the many-layered aspects of extracellular matrices is necessary. The goal of this program is to study the structure, function and regulation of certain agrin domains in health and disease. To achieve this, a combination of structural and biophysical techniques together with biochemical-functional analysis will be performed. Structural information on target proteins in atomic detail obtained from this work will directly contribute to the development of new applications in biomedicine, basic and applied research. Understanding of target proteins and their active sites will guide the structure-based design of diagnostic and therapeutic strategies for the associated disorders.