Mg2+-Dependent Interactions of ATP with the Cystathionine-{beta}-Synthase (CBS) Domains of a Magnesium Transporter [Protein Structure and Folding]

April 6th, 2014 by Hirata, Y., Funato, Y., Takano, Y., Miki, H.

Ancient conserved domain protein/cyclin M (CNNM) family proteins are evolutionarily conserved Mg2+ transporters. However, their biochemical mechanism of action remains unknown. Here, we show the functional importance of the commonly conserved cystathionine-β-synthase (CBS) domains and reveal their unique binding ability to ATP. Deletion mutants of CNNM2 and CNNM4, lacking the CBS domains, are unable to promote Mg2+-efflux. Furthermore, the substitution of one amino acid residue in the CBS domains of CNNM2, which is associated with human hereditary hypomagnesaemia, abrogates Mg2+-efflux. Binding analyses reveal that the CBS domains of CNNM2 directly bind to ATP and not AMP in a manner dependent on the presence of Mg2+, which is inhibited in a similar pattern by the disease-associated amino acid substitution. The requirement of Mg2+ for these interactions is a unique feature among CBS domains, which can be explained by the presence of highly electronegative surface potentials around the ATP-binding site on CNNM2. These results demonstrate that the CBS domains play essential roles in Mg2+-efflux, probably through interactions with ATP. Interactions with ATP, which mostly forms complexes with Mg2+ in cells, may account for the rapid Mg2+ transport by CNNM family proteins.
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