Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors.
The plasma membrane Na+/Ca2+ exchanger (NCX) is almost certainly the major Ca2+ extrusion mechanism in cardiac myocytes. Binding of Na+ and Ca2+ ions to its large cytosolic loop regulates ion transport of the exchanger. We determined the solution structures of two Ca2+ binding domains (CBD1 and CBD2) that, together with an alpha-catenin-like domain (CLD), form the regulatory exchanger loop. CBD1 and CBD2 are very similar in the Ca2+ bound state and describe the Calx-beta motif. Strikingly, in the absence of Ca2+, the upper half of CBD1 unfolds while CBD2 maintains its structural integrity. Together with a 7-fold higher affinity for Ca2+, this suggests that CBD1 is the primary Ca2+ sensor. Specific point mutations in either domain largely allow the interchange of their functionality and uncover the mechanism underlying Ca2+ sensing in NCX.
Hilge
Mark
M
Department of Biophysical Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands. m.hilge@nki.nl
Aelen
Jan
J
Vuister
Geerten W
GW
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D004553:Electric Conductivity; D006801:Humans; D017136:Ion Transport; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000737:chemistry / Q000378:metabolism*
D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium