4p5w
From Proteopedia
Structure of the N- and C-terminal domain fusion of the human mitochondrial aspartate/glutamate carrier Citrin in the calcium-bound state
Structural highlights
Disease[CMC2_HUMAN] Citrullinemia type II;Neonatal intrahepatic cholestasis due to citrin deficiency. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[CMC2_HUMAN] Catalyzes the calcium-dependent exchange of cytoplasmic glutamate with mitochondrial aspartate across the mitochondrial inner membrane. May have a function in the urea cycle.[1] Publication Abstract from PubMedThe 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. Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers.,Thangaratnarajah C, Ruprecht JJ, Kunji ER Nat Commun. 2014 Nov 20;5:5491. doi: 10.1038/ncomms6491. PMID:25410934[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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