INTERMEDIATE FILAMENTS--STRUCTURE, ASSEMBLY AND FUNCTION

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DESCRIPTION: Much information has accumulated over the last 15 years regarding the molecular structure, assembly and cell biology of intermediate filaments (IFs). Over the past few years, cell biology, protein chemistry and molecular genetics have revealed an impressive body of information regarding the structure and assembly of IFs. The IF protein domains elucidated in the 1980's now appear to have important roles in forming and stabilizing filament structure. We now need to know what those roles are and how they are regulated in the cell. Dr. Ip proposes to continue his studies on the mechanisms of formation of IF protein tetrameres, higher order oligomers, filaments and filament networks, and to investigate how these abundant cytoskeletal elements interact functionally with other cellular components. Four specific aims are proposed: (1) to analyze the tail domain of vimentin and its significance in IF assembly; (2) to determine the subunit composition of the neurofilament (NF) building block by in vitro studies, using bacterially expressed recombinant NF proteins; (3) to define specific interacting domains in vimentin IFs, using a two-hybrid system in yeast; and (4) to understand functional interactions between IFs and desmosomes, which together confer structure and stability to tissues. This information is of potential clinical relevance, given that point mutations in IF genes are known to be the basis of several skin diseases.