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J. Biol. Chem., Vol. 277, Issue 28, 25187-25194, July 12, 2002
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From the Section of Molecular Cardiology, Departments of Medicine
and Molecular Pharmacology, Albert Einstein College of Medicine,
Bronx, New York 10461
KCNEs are a family of genes
encoding small integral membrane proteins whose role in governing
voltage-gated potassium channel gating is emerging. Whether each member
of this homologous family interacts with channel proteins in the same
manner is unknown; however, it is clear that the functional effect of
each KCNE on channel gating is different. The specificity of KCNE1
(minK) and KCNE3 control of activation of the potassium channel KvLQT1
maps to a triplet of amino acids within the KCNE transmembrane domain by chimera analysis. We now define the structural determinants of
functional specificity within this triplet. The central amino acid of
the triplet (Thr-58 of minK and Val-72 of KCNE3) is essential for the specific control of voltage-dependent channel
activation characteristics of both minK and KCNE3. Using site-directed
mutations that substitute minK and KCNE3 residues, we determined that a hydroxylated central amino acid is necessary for the slow sigmoidal activation produced by minK. The precise spacing of the hydroxyl group
was required for minK-like activation. An aliphatic amino acid
substituted at position 58 of minK is capable of reproducing KCNE3-like
kinetics and voltage-independent constitutive current activation. The
bulk of the central residue is another critical parameter, indicating
precise positioning of this portion of the KCNE proteins within the
channel complex. An intermediate phenotype produced by several smaller
aliphatic-substituted mutants yields conditional voltage independence
that is distinct from the voltage-dependent gating process,
suggesting that KCNE3 traps the channel in a stable open state. From
these results, we propose a model of KCNE-potassium channel interaction
where the functional consequence depends on the precise contact at a
single amino acid.
A Single Transmembrane Site in the KCNE-encoded Proteins Controls
the Specificity of KvLQT1 Channel Gating*
*
This work was supported in part by NHLBI, National
Institutes of Health Grant R01 HL57388 and the American Heart
Association (to T. V. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 718-430-3370;
Fax: 718-430-8989; E-mail: mcdonald@aecom.yu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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