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J. Biol. Chem., Vol. 280, Issue 1, 494-505, January 7, 2005

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The C-terminal Residues in the Alpha-interacting Domain (AID) Helix Anchor Ca_V Subunit Interaction and Modulation of Ca_V2.3 Channels^*

Laurent Berrou, Yolaine Dodier, Alexandra Raybaud¶, Audrey Tousignant||, Omar Dafi, Joelle N. Pelletier||, and Lucie Parent**

From the Département de Physiologie, Groupe d'étude des Protéines Membranaires, the ^¶Département de Physique, and the ^||Département de Chimie, Université de Montréal, P. O. Box 6128, Downtown Station, Montréal, Québec H3C 3J7, Canada

The alpha-interacting domain (AID) in the I-II linker of high voltage-activated (HVA) Ca²⁺ channel 1 subunits binds with high affinity to Ca_V auxiliary subunits. The recently solved crystal structures of the AID-Ca_V complex in Ca_V1.1/1.2 have revealed that this interaction occurs through a set of six mostly invariant residues Glu/Asp⁶, Leu⁷, Gly⁹, Tyr¹⁰, Trp¹³, and Ile¹⁴ (where the superscript refers to the position of the residue starting with the QQ signature doublet) distributed among three -helical turns in the proximal section of the I-II linker. We show herein that alanine mutations of N-terminal AID residues Gln¹, Gln², Ile³, Glu⁴, Glu⁶, Leu⁷, and Gly⁹ in Ca_V2.3 did not abolish [³⁵S]Ca_V1b or [³⁵S]Ca_V3 subunit overlay binding to fusion proteins nor did they prevent the typical modulation of whole cell currents by Ca_V3. Mutations of the invariant Tyr¹⁰ with either hydrophobic (Ala), aromatic (Phe), or positively charged (Arg, Lys) residues yielded Ca_V3-responsive whole cell currents, whereas mutations with negatively charged residues (Asp, Glu) disrupted Ca_V3 binding and modulation. In contrast, modulation and binding by Ca_V3 was significantly weakened in I14A (neutral and hydrophobic) and I14S (neutral and polar) mutants and eradicated in negatively charged I14D and I14E or positively charged I14R and I14K mutants. Ca_V3-induced modulation was only preserved with the conserved I14L mutation. Molecular replacement analyses carried out using a three-dimensional homology model of the AID helix from Ca_V2.3 suggests that a high degree of hydrophobicity and a restrained binding pocket could account for the strict structural specificity of the interaction site found at position Ile¹⁴. Altogether these results indicate that the C-terminal residues Trp¹³ (1) and Ile¹⁴ anchor Ca_V subunit functional modulation of HVA Ca²⁺ channels.

Received for publication, September 21, 2004 , and in revised form, October 25, 2004.

^* This work was supported by the Canadian Heart and Stroke Foundation and by Canadian Institutes of Health Research Grant MOP 13390 (to L. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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.: 514-343-6673; Fax: 514-343-7146; E-mail: lucie.parent{at}umontreal.ca.

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