Molecular basis for the control of K(+) uptake via KtrAB and KimA by cyclic di-AMP
环二 AMP 通过 KtrAB 和 KimA 控制 K( ) 摄取的分子基础
基本信息
- 批准号:423650202
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Priority Programmes
- 财政年份:2019
- 资助国家:德国
- 起止时间:2018-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The potassium homeostasis is essential for bacterial survival and controlled by the orchestrated function of various K(+) importers and exporters. While different ligands and stimuli have been thought to regulate those, recently, cyclic di-AMP has been identified as overarching regulatory signaling molecule in different Gram-positive bacteria. The production of cyclic di-AMP appears to depend on the K(+) (availability. At an excess of external potassium an increased intracellular cyclic di-AMP level was detected. Vice versa, the uptake and release of potassium was shown to be modulated both by the control of gene expression and protein activity by cyclic di-AMP. In Bacillus subtilis cyclic di-AMP directly binds to K(+) importers KtrAB and KimA leading to their inhibition. However, the underlying mechanism of protein deactivation remains elusive. Here, we will shed light on the molecular principles of cyclic di-AMP binding and transport inhibition. Since K(+) channel KtrAB and potassium-proton symporter KimA supposedly do not share any structural similarities, different binding motifs and regulatory mechanisms are expected. The binding sites and structural consequences of cyclic di-AMP binding will be solved by single particle cryo-electron microscopy and X-ray crystallography. Pulsed EPR spectroscopy will elucidate the nucleotide-dependent conformational dynamics of KtrAB and KimA. Complementary mutational studies in combination with functional assays will identify residues required for nucleotide binding and the subsequent regulation of activity.
钾稳态对细菌的生存至关重要,并受到各种钾(+)输入和输出的协调功能的控制。虽然不同的配体和刺激被认为调节这些,但最近,环二磷酸腺苷已被确定为不同革兰氏阳性细菌的首要调节信号分子。环二磷酸腺苷的产生似乎取决于K(+)的有效性。在外部钾过量时,检测到细胞内环二磷酸腺苷水平升高。反之亦然,钾的吸收和释放被证明是由基因表达和蛋白质活性的控制环二磷酸腺苷调节。在枯草芽孢杆菌中,环二amp直接与K(+)进口商KtrAB和KimA结合,导致其抑制。然而,蛋白质失活的潜在机制仍然难以捉摸。在这里,我们将阐明环二磷酸腺苷结合和运输抑制的分子原理。由于K(+)通道KtrAB和钾质子同调子KimA可能没有任何结构上的相似性,因此它们的结合基序和调节机制可能不同。环二amp结合的结合位点和结构后果将通过单粒子低温电子显微镜和x射线晶体学来解决。脉冲EPR光谱将阐明KtrAB和KimA的核苷酸依赖的构象动力学。结合功能分析的互补突变研究将确定核苷酸结合和随后的活性调节所需的残基。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Professorin Dr. Inga Hänelt其他文献
Professorin Dr. Inga Hänelt的其他文献
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{{ truncateString('Professorin Dr. Inga Hänelt', 18)}}的其他基金
The structural and mechanistic basis of K(+) translocation by the KtrAB system
KtrAB 系统 K( ) 易位的结构和机制基础
- 批准号:
248766510 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Research Grants
Determinants of ion channel versus transporter mechanism in the K(+) transporter superfamily
K( ) 转运蛋白超家族中离子通道与转运蛋白机制的决定因素
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266161834 - 财政年份:2014
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199883430 - 财政年份:2011
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Potassium transporters and channels in bacterial survival
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456202200 - 财政年份:
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