CONFORMATIONAL DYNAMICS IN ION CHANNEL SELECTIVITY AND GATING

离子通道选择性和门控中的构象动力学

• 批准号: 8945932
• 负责人: Katherine Anne Henzler-Wildman
• 金额: $ 29.72万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945932
• 关键词: Action Potentials; Affect; Asthma; Bacillus cereus; Behavior; Binding; Binding Sites; Biochemistry; Biological; Biological Models; Biological Process; Biophysics; Cations; Cells; Charge; Chemicals; Communication; Complex; Coupling; Cyclic Nucleotides; Dehydration; Disease; Electrophysiology (science); Epilepsy; Hydration status; Investigation; Ion Channel; Ions; Kinetics; Length; Ligands; Measurement; Measures; Membrane; Membrane Potentials; Membrane Proteins; Methods; Modeling; Molecular; Mutation; Myocardial dysfunction; N-terminal; Neurologic Dysfunctions; Physiological; Population; Potassium Channel; Process; Property; Protein Dynamics; Resolution; Rest; Role; Site; Slide; Sodium Chloride; Solutions; Structure; Techniques; Testing; Thermodynamics; Time; Vertebral column; Water; base; biophysical properties; hearing impairment; in vivo; interest; mutant; public health relevance; simulation; tool

 DESCRIPTION (provided by applicant): Ion channels control both the resting membrane potential and the action potential in cells. As a result, improper physiological function of ion channels leads to a wide variety of disease states, including cardiac and neurological dysfunction, epilepsy, asthma, hearing loss, and others. Proper ion channel function requires appropriate ion selectivity and channel gating to control ion flux across biological membranes. However, our understanding of these fundamental properties of ion channels is still incomplete because they arise from a complex interplay of structure and dynamics. We will use solution NMR to experimentally test the role of protein dynamics in ion selectivity and gating of the NaK channel from Bacillus cereus solubilized in isotropic bicelles. NaK is an ideal model system because small mutations can shift its selectivity; its structure is similar to eukaryotic potassium channel pore domains, particularly biomedically important cyclic nucleotide gated and HERG potassium channels; and it is highly stable and amenable to structural and biophysical characterization. NMR provides a unique method to simultaneously and quantitatively probe ion channel structure and dynamics with site-specific resolution. The ability of NMR to measure dynamics on diverse timescales and detect transient and lowly populated states allows us to experimentally evaluate the role of protein dynamics on processes ranging from ion selectivity to channel gating. In this proposal we will use NMR studies of NaK to test three aims: Does selectivity arise from cooperative effects of ion binding on backbone dynamics? How does the N-terminal M0 helix regulate NaK gating? What structural and dynamic features allow allosteric communication between the selectivity filter and inner gate in potassium channels?