Molecular basis for actin reorganization by the neuronal protein SPAR

描述(申请人提供)：在中枢神经系统中，兴奋性突触传递主要发生在树突棘，树突上的小突起。脊柱结构和运动的失调与多种病理有关，包括脆性X综合征、唐氏综合症、精神分裂症和药物成瘾。脊柱相关RapGAP(SPAR)是一种多结构域支架蛋白，富含成熟的树突状棘突，通过与肌动蛋白细胞骨架和小GTP酶Rap2的相互作用来调节脊柱的动力学和形态。我的主要目标是确定SPAR介导的树突棘中肌动蛋白细胞骨架重组的分子基础。为此，我将使用生化和生物物理研究，重点是X射线结晶学，以确定SPAR通过与其多种效应蛋白的相互作用来调节脊柱结构变化的分子基础。这将涉及确定以下的三维结构：1)SPAR PDZ结构域单独并与其结合伙伴Kalirin-7复合；以及2)Spar GTP酶激活蛋白(GAP)结构域单独并与GTP酶Rap2复合。这些对Spar结构和功能的揭示将为治疗由脊柱运动异常引起的疾病的潜在疗法奠定基础。 脊椎相关RapGAP(SPAR)是一种与树突棘结构和运动有关的神经元蛋白。有各种疾病，如唐氏综合症、精神分裂症、癫痫和阿尔茨海默病，都源于树突棘的异常生长和结构。因此，研究SPAR及其影响脊柱形态的机制将有助于更好地理解如何治疗和预防这些衰弱的神经疾病。

DESCRIPTION (provided by applicant): In the central nervous system, excitatory synaptic transmission primarily occurs at dendritic spines, small protrusions located on dendrites. Dysregulation of spine structure and motility has been implicated in a variety of pathologies including Fragile-X Syndrome, Down Syndrome, schizophrenia and drug addiction. Spine-associated RapGAP (SPAR) is a multidomain scaffolding protein that is enriched in mature dendritic spines and regulates spine dynamics and morphology through its interactions with the actin cytoskeleton and the small GTPase Rap2. My broad objective is to determine the molecular basis for actin cytoskeleton reorganization in dendritic spines as mediated by SPAR. To this end, I will use biochemical and biophysical studies, with a focus on X-ray crystallography, to determine the molecular basis by which SPAR mediates changes in spine structure through its interactions with its multiple effector proteins. This will involve determining the 3-dimensional structures of the following: 1) the SPAR PDZ domain alone and in complex with its binding partner Kalirin-7; and 2) the SPAR GTPase activating protein (GAP) domain alone and in complex with the GTPase Rap2. These revelations into SPAR structure and function will lay the groundwork for potential therapies to treat the diseases that are caused by abnormal spine motility. Spine-associated RapGAP (SPAR) is a neuronal protein that is implicated in dendritic spine structure and motility. There are various diseases such as Down Syndrome, schizophrenia, epilepsy, and Alzheimer's Disease that originate from abnormal dendritic spine growth and structure. Therefore, investigating SPAR and the mechanisms by which it affects spine morphology will lead to greater understanding of how to treat and prevent these debilitating neurological disorders.