Abstract
Dihydropyridine receptor (DHPR), an L-type Ca2+ channel complex, plays an essential role in muscle contraction, secretion, integration of synaptic input in neurons and synaptic transmission. The molecular architecture of DHPR complex remains elusive. Here we present a 15-Å resolution cryo-electron microscopy structure of the skeletal DHPR/L-type Ca2+ channel complex. The DHPR has an asymmetrical main body joined by a hook-like extension. The main body is composed of a “trapezoid” and a “tetrahedroid”. Homologous crystal structure docking and site-specific antibody labelling revealed that the α1 and α2 subunits are located in the “trapezoid” and the β subunit is located in the “tetrahedroid”. This structure revealed the molecular architecture of a eukaryotic Ca2+ channel complex. Furthermore, this structure provides structural insights into the key elements of DHPR involved in physical coupling with the RyR/Ca2+ release channel and shed light onto the mechanism of excitation-contraction coupling.
Highlights
Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Structural determination of Dihydropyridine receptor (DHPR)/L-type Ca21 channel complex has been hampered since its first purification in 1987 due to the extreme difficulty to obtain chemically pure and physically homogenous protein sample for Xray crystallography or electron microscopy studies
The chemical purity of the protein sample can be confirmed by the cleanness of the SDS-PAGE gel— apart from the five bands belonging to the DHPR complex, there are no other bands apparently recognizable
Summary
We present a 15-Aresolution cryo-electron microscopy structure of the skeletal DHPR/L-type Ca21 channel complex. Structural determination of DHPR/L-type Ca21 channel complex has been hampered since its first purification in 1987 due to the extreme difficulty to obtain chemically pure and physically homogenous protein sample for Xray crystallography or electron microscopy studies.
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