Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins.
Voltage-dependent calcium channels (Ca(V)) open in response to changes in membrane potential, but their activity is modulated by Ca(2+) 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 Ca(2+).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 Ca(2+).CaMs interacting with the pre-IQ regions and a canonical Ca(V)1-IQ-Ca(2+).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 Ca(2+)-dependent inactivation of heterologously expressed Ca(V)1.2 channels.
Fallon
Jennifer L
JL
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Baker
Mariah R
MR
Xiong
Liangwen
L
Loy
Ryan E
RE
Yang
Guojun
G
Dirksen
Robert T
RT
Hamilton
Susan L
SL
Quiocho
Florante A
FA
D020746:Calcium Channels, L-Type / Q000737:chemistry*; D002135:Calcium-Binding Proteins / Q000737:chemistry; D002147:Calmodulin / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D017354:Point Mutation; D017434:Protein Structure, Tertiary
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C)