Gating of ion channels is based on structural transitions between open and closed states. To uncover the chemical basis of individual gates, we performed a comparative experimental and computational analysis between two K+channels, KcvSand KcvNTS. These small viral encoded K+channel proteins, with a monomer size of only 82 amino acids, resemble the pore module of all complex K+channels in terms of structure and function. Even though both proteins share about 90% amino acid sequence identity, they exhibit different open probabilities with ca. 90% in KcvNTSand 40% in KcvS. Single channel analysis, mutational studies and molecular dynamics simulations show that the difference in open probability is caused by one long closed state in KcvS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phes in the cavity of the channel, which blocks ion flux. The frequent occurrence of Ser or Thr based helical kinks in membrane proteins suggests that a similar mechanism could also occur in the gating of other ion channels.

Identification of Intrahelical Bifurcated H-Bonds as a New Type of Gate in K+Channels / O. Rauh, M. Urban, L.M. Henkes, T. Winterstein, T. Greiner, J.L. Van Etten, A. Moroni, S.M. Kast, G. Thiel, I. Schroeder. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - 139:22(2017), pp. 7494-7503. [10.1021/jacs.7b01158]

Identification of Intrahelical Bifurcated H-Bonds as a New Type of Gate in K+Channels

A. Moroni;I. Schroeder
2017

Abstract

Gating of ion channels is based on structural transitions between open and closed states. To uncover the chemical basis of individual gates, we performed a comparative experimental and computational analysis between two K+channels, KcvSand KcvNTS. These small viral encoded K+channel proteins, with a monomer size of only 82 amino acids, resemble the pore module of all complex K+channels in terms of structure and function. Even though both proteins share about 90% amino acid sequence identity, they exhibit different open probabilities with ca. 90% in KcvNTSand 40% in KcvS. Single channel analysis, mutational studies and molecular dynamics simulations show that the difference in open probability is caused by one long closed state in KcvS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phes in the cavity of the channel, which blocks ion flux. The frequent occurrence of Ser or Thr based helical kinks in membrane proteins suggests that a similar mechanism could also occur in the gating of other ion channels.
Catalysis; Chemistry (all); Biochemistry; Colloid and Surface Chemistry
Settore BIO/04 - Fisiologia Vegetale
Cell-type and sununit specific alterations of NMDA receptors in striatum at early stages of Parkinson's disease: from molecular pathogenesis to identification of new pharmacological targets
Noninvasive Manipulation of Gating in Ion Channels
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/554701
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