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¶
* Department of Molecular and Integrative Physiology and 
Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801 USA; 
Beckman Institute, Urbana, Illinois 61801 USA; 
National Center for Supercomputing Applications, Urbana, Illinois 61801 USA; and ¶ Departments of Bioengineering and Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093 USA
Correspondence: Address reprint requests to Shankar Subramaniam, Dept. of Bioengineering, University of California at San Diego, La Jolla, CA 92093-0412. Tel.: 858-822-0986; Fax: 858-822-3752; E-mail: shankar{at}ucsd.edu.
Sequence-function analysis of K+-selective channels was carried out in the context of the 3.2 Å crystal structure of a K+ channel (KcsA) from Streptomyces lividans (Doyle et al., 1998). The first step was the construction of an alignment of a comprehensive set of K+-selective channel sequences forming the putative permeation path. This pathway consists of two transmembrane segments plus an extracellular linker. Included in the alignment are channels from the eight major classes of K+-selective channels from a wide variety of species, displaying varied rectification, gating, and activation properties. Segments of the alignment were assigned to structural motifs based on the KcsA structure. The alignment's accuracy was verified by two observations on these motifs: 1), the most variability is shown in the turret region, which functionally is strongly implicated in susceptibility to toxin binding; and 2), the selectivity filter and pore helix are the most highly conserved regions. This alignment combined with the KcsA structure was used to assess whether clusters of contiguous residues linked by hydrophobic or electrostatic interactions in KcsA are conserved in the K+-selective channel family. Analysis of sequence conservation patterns in the alignment suggests that a cluster of conserved residues is critical for determining the degree of K+ selectivity. The alignment also supports the near-universality of the "glycine hinge" mechanism at the center of the inner helix for opening K channels. This mechanism has been suggested by the recent crystallization of a K channel in the open state. Further, the alignment reveals a second highly conserved glycine near the extracellular end of the inner helix, which may be important in minimizing deformation of the extracellular vestibule as the channel opens. These and other sequence-function relationships found in this analysis suggest that much of the permeation path architecture in KcsA is present in most K+-selective channels. Because of this finding, the alignment provides a robust starting point for homology modeling of the permeation paths of other K+-selective channel classes and elucidation of sequence-function relationships therein. To assay these applications, a homology model of the Shaker A channel permeation path was constructed using the alignment and KcsA as the template, and its structure evaluated in light of established structural criteria.
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