Fig. 4.
Human AQP10 gate opening mechanism. a Cluster and principal component (PC) analysis of membrane-embedded hAQP10 molecular dynamics (MD) simulations with mono (mimicking a relatively high pH) and double (relatively low pH) protonation states of H80 yielding four main clusters (#1–4) of arrangements of the cytoplasmic gate region. A population distribution heat map of the principal components is shown in the central panel, with mono and double protonated frames shown in light blue-to-light blue and green-to-light green gradients, respectively. Simplified, PC1 and PC2 represent the pore-width distances between V76 and L174, and between V76 and H80 (see also Supplementary Figs. 8 and 9). Surroundings panels display crystal structure chains A and D, and representative structures of the MD-predicted clusters (#1–4), from closed to fully open with calculated HOLE profiles shown in traffic-light colors (red-to-green gradient). Indicative pKaH80 values were calculated using PropKa. b Proposed hAQP10 pH-gated glycerol flux mechanism in adipocytes and likely other cell types. Glycerol, but not water, permeation is decreased at pH 7.4. AQP10 glycerol-specific opening is stimulated by pH reduction, triggering H80 protonation that renders the residue to interact with E27. Concerted structural changes of the nearby F85 and the cytoplasmic V76–S77 loop thereby allow glycerol passage