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Structural insights into AQP3 channel closure upon pH and redox changes reveal an autoregulatory molecular mechanism

Huang, Peng LU ; Venskutonytė, Raminta LU ; Wilson, Carter J ; Bsharat, Sara LU ; Prasad, Rashmi B LU orcid ; Gourdon, Pontus LU ; Artner, Isabella LU ; de Groot, Bert L and Lindkvist-Petersson, Karin LU (2025) In Nature Communications 16(1).
Abstract

Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H2O2), a key ROS signaling molecule. Here we elucidate the molecular mechanism of AQP3 and show that its regulatory properties are both pH dependent and autoregulated by H2O2. Using single particle cryo-electron microscopy, we present open and closed conformations of human AQP3. At pH 8.0, the channel adopts an open state, while acidic pH or exposure to H2O2 promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H2O2 transport and establish AQP3 as a key modulator of redox homeostasis... (More)

Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H2O2), a key ROS signaling molecule. Here we elucidate the molecular mechanism of AQP3 and show that its regulatory properties are both pH dependent and autoregulated by H2O2. Using single particle cryo-electron microscopy, we present open and closed conformations of human AQP3. At pH 8.0, the channel adopts an open state, while acidic pH or exposure to H2O2 promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H2O2 transport and establish AQP3 as a key modulator of redox homeostasis in human pancreatic β-cells.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aquaporin 3/metabolism, Humans, Hydrogen-Ion Concentration, Oxidation-Reduction, Hydrogen Peroxide/metabolism, Cryoelectron Microscopy, Homeostasis, Insulin-Secreting Cells/metabolism, Reactive Oxygen Species/metabolism, Protein Conformation
in
Nature Communications
volume
16
issue
1
article number
10997
publisher
Nature Publishing Group
external identifiers
  • scopus:105025412524
  • pmid:41429774
ISSN
2041-1723
DOI
10.1038/s41467-025-67144-2
language
English
LU publication?
yes
additional info
© 2025. The Author(s).
id
a18f3002-cbd5-44dd-9b01-411b26d6ed62
date added to LUP
2025-12-30 08:19:06
date last changed
2026-01-14 05:46:38
@article{a18f3002-cbd5-44dd-9b01-411b26d6ed62,
  abstract     = {{<p>Regulation of intracellular levels of reactive oxygen species (ROS) remains poorly understood. Aquaporin 3 (AQP3) facilitates the membrane transport of hydrogen peroxide (H2O2), a key ROS signaling molecule. Here we elucidate the molecular mechanism of AQP3 and show that its regulatory properties are both pH dependent and autoregulated by H2O2. Using single particle cryo-electron microscopy, we present open and closed conformations of human AQP3. At pH 8.0, the channel adopts an open state, while acidic pH or exposure to H2O2 promotes closure via a large conformational rearrangement of extracellular loop E. These findings reveal a mechanism for autoregulation of H2O2 transport and establish AQP3 as a key modulator of redox homeostasis in human pancreatic β-cells.</p>}},
  author       = {{Huang, Peng and Venskutonytė, Raminta and Wilson, Carter J and Bsharat, Sara and Prasad, Rashmi B and Gourdon, Pontus and Artner, Isabella and de Groot, Bert L and Lindkvist-Petersson, Karin}},
  issn         = {{2041-1723}},
  keywords     = {{Aquaporin 3/metabolism; Humans; Hydrogen-Ion Concentration; Oxidation-Reduction; Hydrogen Peroxide/metabolism; Cryoelectron Microscopy; Homeostasis; Insulin-Secreting Cells/metabolism; Reactive Oxygen Species/metabolism; Protein Conformation}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Structural insights into AQP3 channel closure upon pH and redox changes reveal an autoregulatory molecular mechanism}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-67144-2}},
  doi          = {{10.1038/s41467-025-67144-2}},
  volume       = {{16}},
  year         = {{2025}},
}