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.
| Brown, Breann L; Lord, Dana M; Grigoriu, Simina et al. (2013) The Escherichia coli toxin MqsR destabilizes the transcriptional repression complex formed between the antitoxin MqsA and the mqsRA operon promoter. J Biol Chem 288:1286-94 |
| Davis, Jennifer R; Brown, Breann L; Page, Rebecca et al. (2013) Study of PcaV from Streptomyces coelicolor yields new insights into ligand-responsive MarR family transcription factors. Nucleic Acids Res 41:3888-900 |
| Brown, Breann L; Wood, Thomas K; Peti, Wolfgang et al. (2011) Structure of the Escherichia coli antitoxin MqsA (YgiT/b3021) bound to its gene promoter reveals extensive domain rearrangements and the specificity of transcriptional regulation. J Biol Chem 286:2285-96 |
| Brown, Breann L; Page, Rebecca (2010) Preliminary crystallographic analysis of the Escherichia coli antitoxin MqsA (YgiT/b3021) in complex with mqsRA promoter DNA. Acta Crystallogr Sect F Struct Biol Cryst Commun 66:1060-3 |
