CRYSTALLOGRAPHIC STUDIES OF C2 DOMAINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. C2 domains are common phospholipid binding motifs used by an array of proteins. My lab has successfully crystallized C2 domains from a variety of proteins, and we have solved the structures of some these domains using ultra high resolution diffraction data collected at SSRL. While the fold of these domains is well known, the regulation of C2 domains and their involvement in disease processes are still not understood. Here, we will investigate two proteins that utilize C2 domains to answer the aforementioned questions. The first is a continuation of our previous work with the C2 domains of synaptotagmin 1. Our hypothesis is that the ?un-structured linker? domain, which is N-terminal to the main body of the C2 domain, can interact with the Ca+2 binding pocket of C2A to modify the affinity for calcium ion. The second project involves determining the 3D structure of the 7 C2 domains of human dysferlin. Mutations within these C2 domains are known to cause Limb-Girdle muscular dystrophy in humans, and structural information is essential to understand the etiology of this disease.