Supplemental Data Ca2+ Regulation in the Na+/Ca2+ Exchanger Involves Two Markedly Different Ca2+ Sensors

Model construction of the intact exchanger Considering the individuality of CBD1 and CBD2 as well as the relative proximity of their N- and C-termini, these two domains could be an insertion of a third, membrane-peripheral domain. Indeed, a FASTA search for residues 259-370 of NCX1 against structures deposited within the protein data bank reveals 22-24 % sequence identity with one complete domain of α-catenin (PDB code 1H6G; Yang et al., 2001). Using the program MODELLER 6.0 (Sali and Blundell, 1993) and the 1H6G structure as a template, we calculated a homology model for residues 259-370 thereafter referred to as catenin-like domain (CLD; Figure S2). The model shows the majority of the hydrophobic residues in the core of the domain to be either conserved or conservatively substituted. Several hydrophobic patches at the surface of the CLD may accommodate interactions in the intact molecule, for instance with residues 217-258 and 652-706 that complement the domain and connect the regulatory loop to the TM of the exchanger. In the original report on the molecular cloning of cardiac NCX (Nicoll et al., 1990) Nicoll and coworkers have shown that TM residues Tyr179-Leu201 exhibit 48