Collagen XVIII/BP180:Structural and Functional Studies

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DESCRIPTION (provided by applicant): BP180 is a key component of the epidermal anchoring complex and functions to maintain the adherence of the epidermis to the basement membrane. BP180 has been found to be genetically defective or targeted by the immune system in several blistering skin diseases. Structural studies have revealed that BP180 is a type II transmembrane protein with a long carboxy-terrninal collagenous domain that projects into the extracellular region beneath the epidermal hemidesmosome. The first specific aim of this grant addresses important questions regarding the structure of the BP180 extracellular domain, which exists in the form of an interrupted collagen triple helix. They plan to define the protein segments that are essential for the assembly of the BP180 trimer, and to investigate the structural consequences of BP180 mutations that are associated with inherited disorders of the basement membrane zone. The second specific aim is directed toward identifying the extracellular ligand(s) for BP180. One approach to this problem involves analyzing BP180-transduced cells for alterations in cell-matrix attachment properties. A second approach involves assaying protein-protein interactions using a co-immuno-precipitation protocol. The proposed research project represents a multi-level approach to the study of molecular interactions involved in maintaining the integrity of the cutaneous basement membrane zone. During the award period, the candidate will be able to broaden her research experience in the areas of cell and molecular biology, biochemistry and immunology. The candidate's long-range goals are to continue biochemical and molecular biological studies of other collagen proteins and their mutations in an academic setting.