A Self-Sequestered Calmodulin-like Ca2+ Sensor of Mitochondrial SCaMC Carrier and Its Implication to Ca2+-Dependent ATP-Mg/Pi Transport

The mitochondrial carriers play essential roles in energy metabolism. The short Ca2+-binding mitochondrial carrier (SCaMC) transports ATP-Mg in exchange for P-i and is important for activities that depend on adenine nucleotides. SCaMC adopts, in addition to the transmembrane domain (TMD) that transports solutes, an extramembrane N-terminal domain (NTD) that regulates solute transport in a Ca2+-dependent manner. Crystal structure of the Ca2+-bound NTD reveals a compact architecture in which the functional EF hands are sequestered by an endogenous helical segment. Nuclear magnetic resonance (NMR) relaxation rates indicated that removal of Ca2+ from NTD results in a major conformational switch from the rigid and compact Ca2+-bound state to the dynamic and loose apo state. Finally, we showed using surface plasmon resonance and NMR titration experiments that free apo NTDs could specifically interact with liposome-incorporated TMD, but that Ca2+ binding drastically weakened the interaction. Our results together provide a molecular explanation for Ca2+-dependent ATP-Mg flux in mitochondria.