Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation.

Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation. Pfoh, R., Li, A., Chakrabarti, N., Payandeh, J., Pomès, R., & Pai, E., F. Proceedings of the National Academy of Sciences of the United States of America, 10, 2012.

Paper

Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation. [link]

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Magnesium ions (Mg(2+)) are essential for life, but the mechanisms regulating their transport into and out of cells remain poorly understood. The CorA-Mrs2-Alr1 superfamily of Mg(2+) channels represents the most prevalent group of proteins enabling Mg(2+) ions to cross membranes. Thermotoga maritima CorA (TmCorA) is the only member of this protein family whose complete 3D fold is known. Here, we report the crystal structure of a mutant in the presence and absence of divalent ions and compare it with previous divalent ion-bound TmCorA structures. With Mg(2+) present, this structure shows binding of a hydrated Mg(2+) ion to the periplasmic Gly-Met-Asn (GMN) motif, revealing clues of ion selectivity in this unique channel family. In the absence of Mg(2+), TmCorA displays an unexpected asymmetric conformation caused by radial and lateral tilts of protomers that leads to bending of the central, pore-lining helix. Molecular dynamics simulations support these movements, including a bell-like deflection. Mass spectrometric analysis confirms that major proteolytic cleavage occurs within a region that is selectively exposed by such a bell-like bending motion. Our results point to a sequential allosteric model of regulation, where intracellular Mg(2+) binding locks TmCorA in a symmetric, transport-incompetent conformation and loss of intracellular Mg(2+) causes an asymmetric, potentially influx-competent conformation of the channel.

@article{
 title = {Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation.},
 type = {article},
 year = {2012},
 pages = {5-10},
 websites = {http://www.ncbi.nlm.nih.gov/pubmed/23112165},
 month = {10},
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 abstract = {Magnesium ions (Mg(2+)) are essential for life, but the mechanisms regulating their transport into and out of cells remain poorly understood. The CorA-Mrs2-Alr1 superfamily of Mg(2+) channels represents the most prevalent group of proteins enabling Mg(2+) ions to cross membranes. Thermotoga maritima CorA (TmCorA) is the only member of this protein family whose complete 3D fold is known. Here, we report the crystal structure of a mutant in the presence and absence of divalent ions and compare it with previous divalent ion-bound TmCorA structures. With Mg(2+) present, this structure shows binding of a hydrated Mg(2+) ion to the periplasmic Gly-Met-Asn (GMN) motif, revealing clues of ion selectivity in this unique channel family. In the absence of Mg(2+), TmCorA displays an unexpected asymmetric conformation caused by radial and lateral tilts of protomers that leads to bending of the central, pore-lining helix. Molecular dynamics simulations support these movements, including a bell-like deflection. Mass spectrometric analysis confirms that major proteolytic cleavage occurs within a region that is selectively exposed by such a bell-like bending motion. Our results point to a sequential allosteric model of regulation, where intracellular Mg(2+) binding locks TmCorA in a symmetric, transport-incompetent conformation and loss of intracellular Mg(2+) causes an asymmetric, potentially influx-competent conformation of the channel.},
 bibtype = {article},
 author = {Pfoh, Roland and Li, Angela and Chakrabarti, Nilmadhab and Payandeh, Jian and Pomès, Régis and Pai, Emil F},
 doi = {10.1073/pnas.1209018109},
 journal = {Proceedings of the National Academy of Sciences of the United States of America},
 number = {25}
}

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