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Crystal Structure of Dimeric Cardiac L-Type Calcium Channel Regulatory Domains Bridged by Ca²⁺ ·Calmodulins

Jennifer L. Fallon, Mariah R. Baker, Liangwen Xiong, Ryan E. Loy, Guojun Yang, Robert T. Dirksen, Susan L. Hamilton, Florante A. Quiocho and Richard W. Tsien
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 13 (Mar. 31, 2009), pp. 5135-5140
Stable URL: http://www.jstor.org/stable/40455161
Page Count: 6
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Crystal Structure of Dimeric Cardiac L-Type Calcium Channel Regulatory Domains Bridged by Ca²⁺ ·Calmodulins
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Abstract

Voltage-dependent calcium channels ($Ca_v $) open in response to changes in membrane potential, but their activity is modulated by Ca²⁺ binding to calmodulin (CaM). Structural studies of this family of channels have focused on CaM bound to the IQ motif; however, the minimal differences between structures cannot adequately describe CaM's role in the regulation of these channels. We report a unique crystal structure of a 77-residue fragment of the $Ca_v 1.2\alpha _1 $ subunit carboxyl terminus, which includes a tandem of the pre-IQ and IQ domains, in complex with Ca²⁺·CaM in 2 distinct binding modes. The structure of the $Ca_v 1.2$ fragment is an unusual dimer of 2 coiled-coiled pre-IQ regions bridged by 2 Ca²⁺·CaMs interacting with the pre-IQ regions and a canonical ${\rm{Ca}}_{\rm{v}} 1$-IQ-Ca²⁺ ·CaM complex. Native $Ca_v 1.2$ channels are shown to be a mixture of monomers/dimers and a point mutation in the pre-IQ region predicted to abolish the coiled-coil structure significantly reduces Ca²⁺-dependent inactivation of heterologously expressed $Ca_v 1.2$ channels.

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