Journal
BIOPHYSICAL JOURNAL
Volume 92, Issue 10, Pages 3474-3491Publisher
CELL PRESS
DOI: 10.1529/biophysj.106.100669
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Lactose permease structure is deemed consistent with a mechanical switch device for H+-coupled symport. Because the crystallography-assigned docking position of thiodigalactoside ( TDG) does not make close contact with several amino acids essential for symport; the switch model requires allosteric interactions between the proton and sugar binding sites. The docking program, Autodock 3 reveals other lactose- docking sites. An alternative cotransport mechanism is proposed where His-322 imidazolium, positioned in the central pore equidistant ( 5-7 angstrom) between six charged amino acids, Arg-302 and Lys-319 opposing Glu-269, Glu-325, Asp-237, and Asp-240, transfers a proton transiently to an H-bonded lactose hydroxyl group. Protonated lactose and its dissociation product H3O+ are repelled by reprotonated His-322 and drift in the electrostatic field toward the cytosol. This Brownian ratchet model, unlike the conventional carrier model, accounts for diminished symport by H322N mutant; how H322 mutants become uniporters; why exchanging Lys-319 with Asp-240 paradoxically inactivates symport; how some multiple mutants become revertant transporters; the raised export rate and affinity toward lactose of uncoupled mutants; the altered specificity toward lactose, melibiose, and galactose of some mutants, and the proton dissociation rate of H322 being 100- fold faster than the symport turnover rate.
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