Molecular computation by the CaMKII holoenzyme

CaMKII 全酶的分子计算

基本信息

批准号：
10535139
负责人：
Carolyn Nicole Brown
金额：
$ 3.62万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535139
关键词：
Address Affinity Avidity Binding Biochemical Biochemistry Biophysics Calmodulin Cells Cognition Cognitive Complex Data Development Excitatory Synapse Fluorescence Frequencies Geometry Hippocampus (Brain)Holoenzymes Impairment In Vitro Individual Learning Long-Term Potentiation Mediating Mediator of activation protein Memory Mental Depression Modeling Molecular Molecular Computations Mutate N-Methyl-D-Aspartate Receptors Negative Staining Neurodegenerative Disorders Neurons Phosphotransferases Positioning Attribute Process Proteins Reaction Regulation Role Signal Transduction Spectrum Analysis Stimulus Structure Synapses Synaptic plasticity Variant calmodulin-dependent protein kinase II dimer experimental study insight monomer mutant nervous system disorder neuropsychiatric disorder response spatiotemporal stoichiometry three dimensional structure tool training opportunity

项目摘要

PROJECT SUMMARY Learning, cognition, and memory require dynamic remodeling of hippocampal synapses, which in turn requires Ca2+/calmodulin-dependent kinase II (CaMKII). CaMKII mediates two opposing modes of synaptic plasticity, long term potentiation (LTP) and depression (LTD), that are induced by distinct Ca2+ stimuli. Both low and high Ca2+ induce CaMKII autophosphorylation (p) at T286, that is required for both LTP and LTD. Additionally, LTP requires CaMKII binding to the NMDA receptor subunit, GluN2B, during high [Ca2+] while LTD requires CaMKII autophosphorylation at T305/306 during low [Ca2+]. Further, these three mechanisms can undergo complex cross-regulation which requires the CaMKII 12-meric holoenzyme. Interestingly, pT286 positively regulates both GluN2B binding and pT305/306 while GluN2B binding and pT305/306 are mutually exclusive. It is unknown how these reactions and interactions are spatiotemporally encoded within holoenzymes and thus how LTP versus LTD signal computation is accomplished by CaMKII. For example, it has been shown that pT286 must occur between two neighboring kinase domains in the holoenzyme. It is still unclear what determines a functional kinase domain neighbor. Moreover, in vitro binding studies have shown that CaMKII holoenzymes are required for binding to GluN2B, suggesting that this interaction may require multiple subunits. Still, it is unknown what is the required stoichiometry and subunit geometry required for CaMKII-GluN2B binding. Initial results suggest that the holoenzyme rules for pT286 and GluN2B binding are fundamentally different. Therefore, this proposal will investigate my hypothesis that LTP versus LTD mechanisms are regulated by structurally distinct features within CaMKII holoenzymes. The approach will utilize several CaMKII “structural mutants” that have disrupted holoenzyme structure (hexamers, dimers, and monomers). These mutants will be used as tools to define the spatiotemporal dynamics of autophosphorylation within holoenzymes and the subunit stoichiometry and geometry required for GluN2B binding. The results of this proposal will provide insight into how molecular signal computation underlying the LTP versus LTD decision is encoded within CaMKII holoenzymes.

项目摘要学习，认知和记忆需要动态重塑海马突触，这又需要 Ca2+////// calmodulin-dipentent激酶II（CAMKII）。术语增强（LTP）和抑郁症（LTD），由不同的Ca2+刺激引起。在T286处诱导Camkii自磷酸化（P），这是LTP和LTD所必需的 CAMKII在高[Ca2+]期间与NMDA受体亚基Glun2b结合，而LTD需要CAMKII 在低[Ca2+]的T305/306处的自磷酸化。跨阀需要CAMKII 12-MERIC HOLOENZYME。 glun2b结合和pt305/306，而glun2b结合和pt305/306是互斥的。这些反应和相互作用是在全酶内部编码的，因此LTP与 LTD信号计算是由CAMKII完成的。在全酶中的两个相邻的激酶结构域之间，仍然不清楚什么是确定功能此外，激酶结构域。要与glun2b结合，表明这种相互作用可能需要多个亚基。 CAMKII-GLUN2B结合所需的化学计量和亚基几何形状。 PT286和Glun2b结合的全酶规则是基本的。调查我的假设，即LTP与LTD机制是由结构内的不同特征定制的 camkii全酶将使用干扰全酶结构（六聚体，二聚体和单体）。全酶内自噬的时空动力学和亚基在 Glun2b结合所需的几何形状。 LTP与LTD决策的基础计算是编码CAMKII Holoenzymes中的。