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.
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