The role of water coordination in the pH-dependent gating of hAQP10

Sigurd Friis Truelsen, Julie Winkel Missel, Kamil Gotfryd, Per Amstrup Pedersen, Pontus Gourdon, Kresten Lindorff-Larsen*, Claus Hélix-Nielsen*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Human aquaporin 10 (hAQP10) is an aquaglyceroporin that assists in maintaining glycerol flux in adipocytes during lipolysis at low pH. Hence, a molecular understanding of the pH-sensitive glycerol conductance may open up for drug development in obesity and metabolically related disorders. Control of hAQP10-mediated glycerol flux has been linked to the cytoplasmic end of the channel, where a unique loop is regulated by the protonation status of histidine 80 (H80). Here, we performed unbiased molecular dynamics simulations of three protonation states of H80 to unravel channel gating. Strikingly, at neutral pH, we identified a water coordination pattern with an inverted orientation of the water molecules in vicinity of the loop. Protonation of H80 results in a more hydrophobic loop conformation, causing loss of water coordination and leaving the pore often dehydrated. Our results indicate that the loss of such water interaction network may be integral for the destabilization of the loop in the closed configuration at low pH. Additionally, a residue unique to hAQP10 (F85) reveals structural importance by flipping into the channel in correlation with loop movements, indicating a loop-stabilizing role in the closed configuration. Taken together, our simulations suggest a unique gating mechanism combining complex interaction networks between water molecules and protein residues at the loop interface. Considering the role of hAQP10 in adipocytes, the detailed molecular insights of pH-regulation presented here will help to understand glycerol pathways in these cells and may assist in drug discovery for better management of human adiposity and obesity.
    Original languageEnglish
    Article number183809
    JournalBBA Biomembranes
    Volume1864
    Issue number1
    Number of pages13
    ISSN0005-2736
    DOIs
    Publication statusPublished - 2021

    Keywords

    • Aquaporin
    • Channel gating
    • hAQP10
    • Molecular dynamics
    • Water coordination

    Fingerprint

    Dive into the research topics of 'The role of water coordination in the pH-dependent gating of hAQP10'. Together they form a unique fingerprint.

    Cite this