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

TitleCalcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers.
Publication TypeJournal Article
Year of Publication2014
AuthorsThangaratnarajah, C, Ruprecht, JJ, Kunji, ERS
JournalNat Commun
Volume5
Pagination5491
Date Published2014
ISSN2041-1723
Abstract

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 a calcium-regulated N-terminal domain with eight EF-hands, a mitochondrial carrier domain, and a C-terminal domain. Here we present the calcium-bound and calcium-free structures of the N- and C-terminal domains, elucidating the mechanism of calcium regulation. Unexpectedly, EF-hands 4-8 are involved in dimerization of the carrier and form a static unit, whereas EF-hands 1-3 form a calcium-responsive mobile unit. On calcium binding, an amphipathic helix of the C-terminal domain binds to the N-terminal domain, opening a vestibule. In the absence of calcium, the mobile unit closes the vestibule. Opening and closing of the vestibule might regulate access of substrates to the carrier domain, which is involved in their transport. These structures provide a framework for understanding cases of the mitochondrial disease citrin deficiency.

DOI10.1038/ncomms6491
Alternate JournalNat Commun
Citation Key10.1038/ncomms6491
PubMed ID25410934
PubMed Central IDPMC4250520
Grant ListMC_U105663139 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom