Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers

• DOI: 10.1038/ncomms6491
• Publication Date: 2014-11-20T10:31:34Z
• Authors: Chancievan Thanga...; Jonathan J. Ruprecht; Edmund R. S. Kunji
• Keywords: Aspartic Acid; 0303 health sciences; 03 medical and health sciences; Protein Conformation; Glutamic Acid; Humans; Calcium; Crystallography, X-Ray; Mitochondrial Membrane Transport Proteins; Article; Mitochondria; Protein Structure, Tertiary

The transport activity of human mitochondrial aspartate/glutamate carriers is central to the malate-aspartate shuttle, urea cycle, gluconeogenesis and myelin synthesis. They have a unique three-domain structure, comprising calcium-regulated N-terminal domain with eight EF-hands, carrier domain, C-terminal domain. Here we present calcium-bound calcium-free structures N- domains, elucidating mechanism calcium regulation. Unexpectedly, EF-hands 4-8 are involved in dimerization form static unit, whereas 1-3 calcium-responsive mobile unit. On binding, an amphipathic helix binds opening vestibule. In absence calcium, unit closes Opening closing vestibule might regulate access substrates which their transport. These provide framework for understanding cases disease citrin deficiency.