MKP5 allostery in MAPK regulation and signaling in the heart

MKP5 变构在心脏 MAPK 调节和信号传导中的作用

基本信息

  • 批准号:
    10375784
  • 负责人:
  • 金额:
    $ 62.03万
  • 依托单位:
  • 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:
    2022-01-18 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT The catalytic activity and specificity of the mitogen-activated protein kinase (MAPK) phosphatases (MKPs) is governed through their ability to interact with the MAPKs. The MKPs set the fidelity and kinetics of MAPK signaling by regulating, in a spatially distinct manner, both the magnitude and duration of MAPK activity. However, these regulatory mechanisms alone are insufficient to explain the complexity of MKP/MAPK- mediated signaling. This is exemplified by the observation that inactivation of MKPs deliver unique, and in some cases, non-obvious physiological and pathophysiological outcomes that has led to the realization that MKPs represent valuable therapeutic targets for the treatment of certain diseases. We have found that MKP5, which directly dephosphorylates p38 MAPK and JNK, is involved in the development of cardiac fibrosis, a serious sequalae that precedes heart failure. Mice lacking MKP5 are protected from the development of cardiac fibrosis and heart failure in a model of pressure overload. A high throughput small molecule screen identified a first-in-class inhibitor of MKP5. Resolution of the co-crystal structure of the inhibitor in complex with MKP5 revealed that the inhibitor bound to an allosteric site on MKP5. We hypothesize that the MKP5 allosteric site represents an additional mode of MKP5 regulation that governs signaling specificity and that this allosteric site represents the “Achilles heel” of MKP5 for small molecule targeting. The broad goal of this work is two-fold. First, we will define the molecular basis for how the allosteric site regulates MKP5 catalysis and MAPK signaling. Second, whether disruption of the allosteric site produces outcomes in a disease context that provide proof-of-concept that if successfully “drugged” this site represents a platform for development of first-in-class MKP inhibitors. We will execute the specifics of these two broad goals through three specific aims. Aim 1, will employ structural biology and biophysical approaches to elucidate the structural determinants and binding mechanisms conferred by the MKP5 allosteric site to determine how this site regulates MKP5 catalysis and MAPK binding. A co-complex between MKP5 and p38 MAPK will be obtained to define how p38 MAPK modulates MKP5 through the allosteric site. In Aim 2, the effects of mutants in the MKP5 allosteric site on MAPK signaling will be determined by generating knockin cells harboring MKP5 allosteric site mutants using CRISPR-Cas approaches. The specificity of the MKP5 allosteric site to “fine-tune” MAPK-mediated signaling will be determined using non-biased phosphoproteomic and transcriptomic approaches. In Aim 3, the effects of targeting the MKP5 allosteric site in cardiac fibrosis and heart failure will be determined through the generation of a novel MKP5 allosteric site mutant knock-in mouse. These studies will define a new mode of operation for MKP5 that will provide information on the actions of the allosteric site at the atomic level. How the MKP5 allosteric site impacts physiological signaling and the validity of the allosteric site as a “druggable” target in disease therapeutics will be defined.
摘要

项目成果

期刊论文数量(0)
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Anton M Bennett其他文献

Anton M Bennett的其他文献

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{{ truncateString('Anton M Bennett', 18)}}的其他基金

MKP5 allostery in MAPK regulation and signaling in the heart
MKP5 变构在心脏 MAPK 调节和信号传导中的作用
  • 批准号:
    10552036
  • 财政年份:
    2022
  • 资助金额:
    $ 62.03万
  • 项目类别:
Dual-specificity phosphatase action in muscle disease
肌肉疾病中的双特异性磷酸酶作用
  • 批准号:
    10621754
  • 财政年份:
    2022
  • 资助金额:
    $ 62.03万
  • 项目类别:
Dual-specificity phosphatase action in muscle disease
肌肉疾病中的双特异性磷酸酶作用
  • 批准号:
    10342959
  • 财政年份:
    2022
  • 资助金额:
    $ 62.03万
  • 项目类别:
Yale Post-Baccalaureate Research Education Program
耶鲁大学学士后研究教育计划
  • 批准号:
    10686863
  • 财政年份:
    2021
  • 资助金额:
    $ 62.03万
  • 项目类别:
Yale Post-Baccalaureate Research Education Program
耶鲁大学学士后研究教育计划
  • 批准号:
    10474267
  • 财政年份:
    2021
  • 资助金额:
    $ 62.03万
  • 项目类别:
Yale Post-Baccalaureate Research Education Program
耶鲁大学学士后研究教育计划
  • 批准号:
    10113213
  • 财政年份:
    2021
  • 资助金额:
    $ 62.03万
  • 项目类别:
Signaling by Shp2 mutants in RASopathies
RASopathies 中 Shp2 突变体的信号传导
  • 批准号:
    9889163
  • 财政年份:
    2018
  • 资助金额:
    $ 62.03万
  • 项目类别:
MKP5 in Dystrophic Muscle Disease
MKP5 在营养不良性肌肉疾病中的作用
  • 批准号:
    9003031
  • 财政年份:
    2015
  • 资助金额:
    $ 62.03万
  • 项目类别:
MKP5 in Dystrophic Muscle Disease
MKP5 在营养不良性肌肉疾病中的作用
  • 批准号:
    8839100
  • 财政年份:
    2015
  • 资助金额:
    $ 62.03万
  • 项目类别:
Signaling by gain-of-function SHP-2 mutants in Noonan syndrome
努南综合征中功能获得性 SHP-2 突变体的信号传导
  • 批准号:
    8622206
  • 财政年份:
    2012
  • 资助金额:
    $ 62.03万
  • 项目类别:

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通过原子图分析进行功能残基的变构位点预测和传递
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