CRYSTALLOGRAPHIC STUDIES OF C2 DOMAINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 C2结构域是一系列蛋白质共同使用的磷脂结合基序。我的实验室已经成功地从各种蛋白质中结晶了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一些这些结构域的结构。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，我们将研究两个利用C2结构域来回答上述问题的蛋白质。第一个是我们之前对synaptopagmin1的C2结构域的研究的继续。结构域位于C2结构域主体的N端，可以与C2a的钙结合口袋相互作用，从而改变对钙离子的亲和力。第二个项目涉及确定人类干扰素的7个C2结构域的3D结构。已知这些C2结构域的突变会导致人类四肢-吉氏肌营养不良，结构信息对于了解这种疾病的病因是必不可少的。

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.