期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 21, 页码 5426-5431出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1800559115
关键词
C-type inactivation; KcsA; allosteric coupling; Kv 1.5; Shaker channel
资金
- Center for Membrane Protein Research-Texas Tech University Health Sciences Center Seed Grant
- American Heart Association Grant [11SDG5440003]
- National Institutes of Health Grant [1RO1GM097159-01A1]
- Welch Foundation Grant [BI-1757]
The selectivity filter and the activation gate in potassium channels are functionally and structurally coupled. An allosteric coupling underlies C-type inactivation coupled to activation gating in this ion-channel family (i.e., opening of the activation gate triggers the collapse of the channel's selectivity filter). We have identified the second Threonine residue within the TTVGYGD signature sequence of K+ channels as a crucial residue for this allosteric communication. A Threonine to Alanine substitution at this position was studied in three representative members of the K+-channel family. Interestingly, all of the mutant channels exhibited lack of C-type inactivation gating and an inversion of their allosteric coupling (i.e., closing of the activation gate collapses the channel's selectivity filter). A state-dependent crystallographic study of KcsA-T75A proves that, on activation, the selectivity filter transitions from a nonconductive and deep C-type inactivated conformation to a conductive one. Finally, we provide a crystallographic demonstration that closed-state inactivation can be achieved by the structural collapse of the channel's selectivity filter.
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