期刊
BIOPHYSICAL JOURNAL
卷 113, 期 5, 页码 1025-1036出版社
CELL PRESS
DOI: 10.1016/j.bpj.2017.07.025
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资金
- National Science Foundation (NSF) [MCB-1519640]
- National Institute on Minority Health and Health Disparities from the National Institutes of Health (NIH) [8G12MD007603]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1519640] Funding Source: National Science Foundation
The ubiquitously expressed CLC chloride transporters are involved in a great variety of physiological functions. The CLC protein fold is shared by Cl-channels and 2Cl-:1H(+) antiporters. The antiporters pump three charges per cycle across the membrane with two CI- ions moving in the opposite direction of one proton. Multiconformational continuum electrostatics was used to calculate the coupled thermodynamics of the protonation of the extracellular-facing gating Glu (E-x) and Cl-binding to the external (Sr) and central (S-c) sites in CLC-ec1, the Escherichia coli exchanger. S-x, S-c, and E-x are buried within the protein where the intersection of two helix N-termini creates a region with a strong, localized positive potential for anion binding. Our chemical potential titrations describe the thermodynamic linkage for binding the Cl-to each site and protons to E-x. We find that the 2Cl(-):1 H+ binding stoichiometry is a result of Cl(-)binding to S-x requiring H+ binding to E-x, whereas Cl-binding to S-c does not lead to proton uptake. When Sx binds a Cl-, the protonated E-x moves upward, out of the positive helix cage. The increasing E-x proton affinity on binding the first Cl reduces the cost of binding the second Cl at either S-x or S-c. Despite the repulsion among the anions, the lowest energy states have two anions bound in the helix cage. The state with no Cl-is not favored electrostatically, but relies on E-x blocking S-x and on the central residues Y445 and S107 blocking S-c.
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