The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif.
The Na+/Ca2+ exchanger is a plasma membrane protein that regulates intracellular Ca2+ levels in cardiac myocytes. Transport activity is governed by Ca2+, and the primary Ca2+ sensor (CBD1) is located in a large cytoplasmic loop connecting two transmembrane helices. The binding of Ca2+ to the CBD1 sensory domain results in conformational changes that stimulate the exchanger to extrude Ca2+. Here, we present a crystal structure of CBD1 at 2.5A resolution, which reveals a novel Ca2+ binding site consisting of four Ca2+ ions arranged in a tight planar cluster. This intricate coordination pattern for a Ca2+ binding cluster is indicative of a highly sensitive Ca2+ sensor and may represent a general platform for Ca2+ sensing.
Nicoll
Debora A
DA
Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Sawaya
Michael R
MR
Department of Chemistry and Biochemistry, UCLA-Department of Energy Center for Genomics and Proteomics, Molecular Biology Institute, University of California, Los Angeles, California 90095.
Kwon
Seunghyug
S
Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Cascio
Duilio
D
Department of Chemistry and Biochemistry, UCLA-Department of Energy Center for Genomics and Proteomics, Molecular Biology Institute, University of California, Los Angeles, California 90095.
Philipson
Kenneth D
KD
Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
Abramson
Jeff
J
Department of Physiology and the Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, California 90095. Electronic address: jabramson@mednet.ucla.edu.
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D004285:Dogs; D032383:Myocytes, Cardiac / Q000737:chemistry; D011487:Protein Conformation; D044169:Receptors, Calcium-Sensing / Q000737:chemistry*; D019831:Sodium-Calcium Exchanger / Q000737:chemistry*
D002135:Calcium-Binding Proteins; D044169:Receptors, Calcium-Sensing; D019831:Sodium-Calcium Exchanger; D002118:Calcium