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-手型钙结合基序。它们的特征在于细胞类型和细胞周期特异性表达，以及在一些神经和炎性疾病和某些癌症中的失调表达。在结构水平上，S100通过其独特的结构与其他EF手蛋白区分开。迄今为止，对这些蛋白质的结构生物学研究提供了关于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环境中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伴侣的活性并参与信号转导途径。一个多学科的战略，包括生物化学和结构的方法，将被利用。这项研究计划的广泛，长期目标是确定S100蛋白的细胞活性的结构基础，以便更好地了解它们在健康和疾病中的作用。 S100A6已被证明与Siah-1相互作用蛋白（SIP）在物理上和功能上相互作用，SIP是E3连接酶复合物的必要组分，E3连接酶复合物泛素化β-连环蛋白作为胚胎发生期间细胞增殖调节的一部分。目的一：明确S100 A6与SIP相互作用的结构基础;确定S100蛋白的三个I结构域的结构和结构组织;研究S100蛋白的结合如何影响SIP结构域的组织及其与其他SIP结合蛋白的相互作用。几种S100蛋白与晚期糖基化终产物（AGEs）的受体β-D相互作用。AGE结合到糖尿病中的动脉粥样硬化的进展与糖尿病有关。在目标2中，我们提出：（i）定义的结构基础的相互作用的S100蛋白的S100A6的结合如何影响的胞外结构域的S100蛋白和AGEs的结合之间的串扰的特征。这些结果将提供的见解的结构基础上的S100功能的AGE受体信号，第一个这样的信息S100蛋白在细胞外环境中的功能。

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.