3us9 | pdb_00003us9

Crystal Structure of the NCX1 Intracellular Tandem Calcium Binding Domains(CBD12)

spinqualitylabelsall models 3us9, resolution 2.68Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3us9 is a 1 chain structure with sequence from Canlf. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CA Gene: SLC8A1 (CANLF) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NAC1_CANFA] Rapidly transports Ca(2+) during excitation-contraction coupling. Ca(2+) is extruded from the cell during relaxation so as to prevent overloading of intracellular stores. Publication Abstract from PubMed Na(+)/Ca(2+) exchanger (NCX) proteins mediate Ca(2+)-fluxes across the cell membrane to maintain Ca(2+) homeostasis in many cell types. Eukaryotic NCX contains Ca(2+)-binding regulatory domains, CBD1 and CBD2. Ca(2+) binding to a primary sensor (Ca3-Ca4 sites) on CBD1 activates mammalian NCXs, whereas CALX, a Drosophila NCX ortholog, displays an inhibitory response to regulatory Ca(2+). To further elucidate the underlying regulatory mechanisms, we determined the 2.7 A crystal structure of mammalian CBD12-E454K, a two-domain construct that retains wild-type properties. In conjunction with stopped-flow kinetics and SAXS (small-angle X-ray scattering) analyses of CBD12 mutants, we show that Ca(2+) binding to Ca3-Ca4 sites tethers the domains via a network of interdomain salt-bridges. This Ca(2+)-driven interdomain switch controls slow dissociation of "occluded" Ca(2+) from the primary sensor and thus dictates Ca(2+) sensing dynamics. In the Ca(2+)-bound conformation, the interdomain angle of CBD12 is very similar in NCX and CALX, meaning that the interdomain distances cannot account for regulatory diversity in NCX and CALX. Since the two-domain interface is nearly identical among eukaryotic NCXs, including CALX, we suggest that the Ca(2+)-driven interdomain switch described here represents a general mechanism for initial conduction of regulatory signals in NCX variants. A common Ca2+-driven interdomain module governs eukaryotic NCX regulation.,Giladi M, Sasson Y, Fang X, Hiller R, Buki T, Wang YX, Hirsch JA, Khananshvili D PLoS One. 2012;7(6):e39985. doi: 10.1371/journal.pone.0039985. Epub 2012 Jun 29. PMID:22768191 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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