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The structural basis for glycerol permeation by human AQP7
Li Zhang1, Deqiang Yao2, Ying Xia3
1CAS Center for Excellence on Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201210, China.
Science Bulletin
|January 19, 2023
Summary
Human aquaporin 7 (AQP7) facilitates glycerol transport, crucial for metabolism in various tissues. Its structure reveals a glycerol binding site that controls flux, offering insights into glycerol channel function.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Physiology
Background:
- Human aquaporin 7 (AQP7) is a glycerol channel involved in glycerol metabolism in adipocytes, pancreatic islets, muscles, and kidney tubules.
- AQP7 exhibits unique structural features, including a less conserved NPA motif and aromatic residues at the Ar/R selectivity filter, compared to other aquaglyceroporins.
- Understanding the structural basis of AQP7's glycerol conductance is essential for elucidating its physiological role.
Purpose of the Study:
- To determine the high-resolution crystal structure of human AQP7.
- To elucidate the structural mechanisms underlying glycerol transport and regulation by AQP7.
- To investigate the role of specific residues, such as R229, in glycerol binding and channel gating.
Main Methods:
- X-ray crystallography was employed to determine the structure of human AQP7 at 3.7 Å resolution.
- Glycerol uptake assays were performed on human AQP7, AQP3, and AQP10 under physiological conditions.
- Molecular dynamics simulations were conducted on the human AQP7 structure.
Main Results:
- The crystal structure revealed a substrate binding pocket near the Ar/R selectivity filter, where a glycerol molecule is bound and stabilized by R229.
- Glycerol uptake assays confirmed significant glycerol transport activity for AQP7, AQP3, and AQP10.
- Structural analysis and simulations showed AQP7 in a closed conformation, with the permeation pathway gated at both the exoplasmic (Ar/R filter) and cytoplasmic sides.
- Glycerol binding at the Ar/R filter was identified as critical for controlling glycerol flux by inducing conformational changes in the channel.
Conclusions:
- The structure of human AQP7 provides a detailed molecular understanding of glycerol binding and channel gating.
- Glycerol binding to the Ar/R filter plays a key role in regulating glycerol permeation through AQP7.
- These findings enhance our comprehension of glycerol transport mechanisms and the physiological functions of aquaglyceroporins.
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