S100 Proteins: Structural Basis of Functional Properties

描述（由申请人提供）：s100是一组独特的蛋白质，含有EF-hand钙结合基序。它们的特点是细胞类型和细胞周期特异性表达，以及在一些神经和炎症疾病以及某些癌症中不受调节的表达。在结构水平上，Sl00s以其独特的结构与其他EF-hand蛋白区别开来。迄今为止，对这些蛋白质的结构生物学研究已经提供了S100结构和对结合钙的反应的详细信息，但对这些蛋白质如何在更大的细胞背景下影响信号传导的了解甚少。本研究旨在通过研究一个细胞内和一个细胞外信号系统，了解S100蛋白如何调节其结合伙伴的活性并参与信号转导途径。将采用包括生物化学和结构方法的多学科战略。这项研究计划的长远目标是确定S100蛋白细胞活动的结构基础，以便更好地了解它们在健康和疾病中的作用。

DESCRIPTION (provided by applicant): S100s are a unique group of proteins containing the EF-hand calcium binding motif. They are characterized by cell-type and cell cycle specific expression, as well as deregulated expression in some neurological and inflammatory disorders and certain cancers. On the structural level, Sl00s are distinguished from other EF-hand proteins by their unique architecture. To date, structural biology studies on these proteins have provided detailed information on the S100 structure and the response to binding calcium, but little insight into how these proteins affect signaling within a larger cellular context. This proposal is aimed at understanding how S100 proteins modulate the activities of their binding partners and participate in signal transduction pathways, by studying one intracellular and one extracellular signaling system. A multi-disciplinary strategy, that incorporates biochemical and structural approaches, will be utilized. The broad, long-term objective of this research program is to determine the structural basis for the cellular activities of the S100 proteins, so that their roles in health and disease may be better understood. S100A6 has been shown to interact physically and functionally with Siah-1 interacting protein (SIP), which Is an essential component of an E3 ligase complex that ubiquitinates beta-catenin as part of the regulation of cell proliferation during embryogenesis. In Aim 1, we propose to: (i) define the structural basis for the interaction of S100A6 and SIP; (ii) determine the structures and the structural organization of SlP's three Idomains; (iii) examine how S100 protein binding affects the organization of SIP domains and its interactions with other SIP binding proteins. Several S100 proteins interact with RAGE, a receptor for Advanced Glycation Endproducts (AGEs). AGE binding to RAGE has been linked with the progression of atherosclerosis in diabetes. In Aim 2, we propose to: (i) define the structural basis for the interaction of RAGE with S100 proteins; (ii) determine how binding of S100A6 affects the structural organization of the extracellular domains of RAGE; (iii) characterize the cross-talk between binding of S100 proteins and AGEs. These results will provide the insights on the structural basis of S100 function in AGE receptor signaling, the first such information on function of S100 proteins in the extracellular milieu.