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Volume 271, Number 49, Issue of December 6, 1996 pp. 31013-31016
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
The Signature Sequence of Voltage-gated Potassium Channels Projects into the External Vestibule

(Received for publication, August 7, 1996, and in revised form, September 13, 1996)

Jayashree Aiyar , James P. Rizzi , George A. Gutman ^§ and K. George Chandy

From the Departments of Physiology and Biophysics and ^§ Microbiology and Molecular Genetics, University of California, Irvine, California 92697 and  Amgen Inc., Boulder, Colorado 80301

A highly conserved motif, GYGD, contributes to the formation of the ion selectivity filter in voltage-gated K⁺ channels and is thought to interact with the scorpion toxin residue, Lys²⁷. By probing the pore of the Kv1.3 channel with synthetic kaliotoxin-Lys²⁷ mutants, each containing a non-natural lysine analog of a different length, and using mutant cycle analysis, we determined the spatial locations of Tyr⁴⁰⁰ and Asp⁴⁰² in the GYGD motif, relative to His⁴⁰⁴ located at the base of the outer vestibule. Our data indicate that the terminal amines of the shorter Lys²⁷ analogs lie close to His⁴⁰⁴ and to Asp⁴⁰², while Lys²⁷ itself interacts with Tyr⁴⁰⁰. Based on these data, we developed a molecular model of this region of the channel. The junction between the outer vestibule and the pore is defined by a ring (~8-9-Å diameter) formed from alternating Asp⁴⁰² and His⁴⁰⁴ residues. Tyr⁴⁰⁰ lies 4-6 Å deeper into the pore, and its interaction with kaliotoxin-Lys²⁷ is in competition with K⁺ ions. Studies with dimeric Kv1.3 constructs suggest that two Tyr⁴⁰⁰ residues in the tetramer are sufficient to bind K⁺ ions. Thus, at least part of the K⁺ channel signature sequence extends into a shallow trough at the center of a wide external vestibule.

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