A possible molecular mechanism of hanatoxin binding-modified gating in voltage-gated K- channels
Resource
JOURNAL OF MOLECULAR RECOGNITION 16(6); 392-395
Journal
JOURNAL OF MOLECULAR RECOGNITION 16(6);
Pages
392-395
Date Issued
2004
Date
2004
Author(s)
Lou, Kuo-Long
DOI
922311B002101
Abstract
Potassium channels are membrane proteins that regulate
potassium flux across the cell membrane. They contribute to
diverse cell functions from control of membrane potential
and excitability of neurons and muscles to regulation of cell
volume and osmotic balance. The voltage-gated K-
channels (Kv) comprise a large family of tetramers that
open and close in response to changes in membrane voltage.
Six putative transmembrane segments termed S1–S6 are
included in each subunit of the tetramer. Among them, S5
and S6 assemble the central pore domain forming the K-
selective ion conduction pathway (MacKinnon and Miller,
1989; MacKinnon and Yellen, 1990; Hartmann et al., 1991;
MacKinnon, 1991; Yellen et al., 1991; Yool and Schwarz,
1991; Liman et al., 1992; Heginbotham et al., 1994;
Ranganathan et al., 1996; Armstrong and Hille, 1998). The
first four transmembrane segments (S1–S4) of voltage-gated
K channels do not contribute to the simple pore, and
appear to underlie their unique voltage-sensing capabilities
(Armstrong and Hille, 1998). S4 is an unusual transmembrane
segment that contains a large number of basic
residues, which has been suggested by considerable study
be strongly involved in sensing changes in membrane
voltage (Liman et al., 1991; Papazian et al., 1991; Perozo et
al., 1994; Aggarwal and MacKinnon, 1996; Bezanilla et al.,
1996; Larsson et al., 1996; Mannuzzu et al., 1996; Seoh et
al., 1996; Yang et al., 1996; Yusaf et al., 1996; Smith-
Maxwell et al., 1998a, 1998b; Ledwell and Aldrich, 1999).
The C-terminal part of S3 segment (S3C) is of particular
interest because it has been identified as an important region
for interaction with various gating modifier toxins (Rogers
et al., 1996; Swartz and MacKinnon, 1997a, 1997b; Li-
Smerin and Swartz, 1998, 2000; Winterfield and Swartz,2000). Among them, hanatoxin (HaTx1), a 35-amino acid
protein isolated from tarantula venom (Swartz and Mac-
Kinnon, 1995), shows an inhibition on drk1 (Kv2.1) by
shifting activation to more depolarized voltages (Swartz and
MacKinnon, 1997a, 1997b). Investigation on the structural
and functional correlation between hanatoxin and voltagegated
potassium channels has provided quite useful
information in analyzing the roles of S3c in K-channel
gating (Takahashi et al., 2000; Li-Smerin and Swartz, 1998,
2000, 2001).
Previously we have reported (Huang et al., 2001; Lou et
al., 2002; Huang, 2002) a docking simulation study
describing the exact binding residues required for HaTx1–
drk1 interaction and the derived conformational change
resulting from binding. However, while further considering
the movement presumably towards S4 upon conformational
change (Huang et al., 2001), together with the specific
binding pocket close to the external crevice depicted from the
detailed residue analysis (Lou et al., 2002), we noticed that
the structural roles of S3C–S4 proximity in interfering with
S4 translocation must be clarified, especially in terms of the
length of S3–S4 linker (Mathur et al., 1997; Swartz and
MacKinnon, 1997a, 1997b; Gonzalez et al., 2000). In this
study, thereby, we extensively and comprehensively compare
the docking simulation results of drk1 S3C–HaTx1 to the
substitution with shaker S3C sequence. The mutual influence
of the proximity of S3C–S4N region is thus discussed.
Publisher
臺北市：國立臺灣大學醫學院口腔生物科學研究所
Type
journal article
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