title: Structural basis for Ca2+ regulation in the Na+/Ca2+ exchanger.
abstract: Binding of Na+ and Ca2+ ions to the large cytosolic loop of the Na+/Ca2+ exchanger (NCX) regulates its ion transport across the plasma membrane. 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 constitute a novel Ca2+-binding motif and are very similar in the Ca2+-bound state. Strikingly, in the absence of Ca2+ the upper half of CBD1 unfolds while CBD2 maintains its structural integrity. Together with a sevenfold 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.
authors.affiliation: Department of Biophysical Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands. hilge@nmr.ru.nl
authors.forename: Mark
authors.initials: M
authors.lastname: Hilge
authors.forename: Jan
authors.initials: J
authors.lastname: Aelen
authors.forename: Anastassis
authors.initials: A
authors.lastname: Perrakis
authors.forename: Geerten W
authors.initials: GW
authors.lastname: Vuister
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D019831:Sodium-Calcium Exchanger / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019831:Sodium-Calcium Exchanger; D002118:Calcium