CRYSTALLOGRAPHIC STUDIES OF C2 DOMAINS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 C2结构域是一系列蛋白质使用的常见磷脂结合基序。 我的实验室已经成功地从各种蛋白质中结晶出C2结构域，并且我们已经使用SSRL收集的超高分辨率衍射数据解决了其中一些结构域的结构。虽然这些结构域的折叠是众所周知的，但C2结构域的调节及其在疾病过程中的参与仍然不清楚。在这里，我们将研究两种利用C2结构域来回答上述问题的蛋白质。第一个是我们以前的工作与突触结合蛋白1的C2域的延续。 我们的假设是？非结构化连接器？C2结构域的N-末端可以与C2A的Ca +2结合口袋相互作用以改变对钙离子的亲和力。 第二个项目涉及确定人dysferlin的7个C2结构域的3D结构。 已知这些C2结构域内的突变会导致人类的肢带型肌营养不良症，并且结构信息对于理解这种疾病的病因至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.