Structures of Gating Intermediates in a K+ channel期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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Structures of Gating Intermediates in a K+ channel

Institution:	1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel;2. Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel;3. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel;1. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany;4. Department of Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany;5. Centre for Chronic Immunodeficiency (CCI), University Clinics and University of Freiburg, Freiburg, Germany;6. National Facility for Protein Science in Shanghai, ZhangJiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201203, China;7. School of Pharmacy, Tianjin Medical University, Tianjin 300070, China;1. Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA;2. Center for Advanced Biotechnology and Medicine and the Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, NJ 08854, USA;1. Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;2. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;1. Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Uniwersytetu Poznańskiego 6, 61-614 Poznań, Poland;2. T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA;3. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznań, Poland

Abstract:	Regulation of ion conduction through the pore of a K⁺ channel takes place through the coordinated action of the activation gate at the bundle crossing of the inner helices and the inactivation gate located at the selectivity filter. The mechanism of allosteric coupling of these gates is of key interest. Here we report new insights into this allosteric coupling mechanism from studies on a W67F mutant of the KcsA channel. W67 is in the pore helix and is highly conserved in K⁺ channels. The KcsA W67F channel shows severely reduced inactivation and an enhanced rate of activation. We use continuous wave EPR spectroscopy to establish that the KcsA W67F channel shows an altered pH dependence of activation. Structural studies on the W67F channel provide the structures of two intermediate states: a pre- open state and a pre-inactivated state of the KcsA channel. These structures highlight key nodes in the allosteric pathway. The structure of the KcsA W67F channel with the activation gate open shows altered ion occupancy at the second ion binding site (S2) in the selectivity filter. This finding in combination with previous studies strongly support a requirement for ion occupancy at the S2 site for the channel to inactivate.

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