Molecular basis for actin reorganization by the neuronal protein SPAR

描述（由申请人提供）：在中枢神经系统，兴奋性突触传递主要发生在树突棘，树突上的小突起。脊柱结构和运动失调与多种疾病有关，包括脆性x综合征、唐氏综合征、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，在成熟树突棘中丰富，并通过与肌动蛋白细胞骨架和小GTPase Rap2的相互作用调节脊柱动力学和形态。我的主要目标是确定由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，我将利用生物化学和生物物理研究，重点是x射线晶体学，来确定SPAR通过与其多种效应蛋白的相互作用介导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)单独的SPAR PDZ结构域及其结合伙伴Kalirin-7的复合物；2) SPAR GTPase激活蛋白（GAP）结构域单独或与GTPase Rap2复合物。这些对SPAR结构和功能的揭示将为治疗由脊柱异常运动引起的疾病的潜在疗法奠定基础。

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.