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

DOI: 10.1038/ncomms6491 DOI Help
PMID: 25410934 PMID Help

Authors: Chancievan Thangaratnarajah (The Medical Research Council) , Jonathan Ruprecht (The Medical Research Council) , Edmund Kunji (The Medical Research Council)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 5

State: Published (Approved)
Published: November 2014
Diamond Proposal Number(s): 6641 , 8547

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 24/02/2015 09:56

Documents:
ncomms6491.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)