The Structural Basis for Glycerol Permeation by human AQP7

Zhang, Li; Yao, Deqiang; Zhou, Fu; Zhang, Qing; Xia, Ying; Wang, Qian; Qin, An; Zhao, Jie; Li, Dianfan; Zhou, Lu; Cao, Yu

doi:10.1101/858332

Cited by 3 publications

(3 citation statements)

References 34 publications

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“…The two NCSrelated AQP7 dimers comprise two monomers with 3 glycerol molecules, and two monomers with 2 glycerol molecules in the monomeric pore. A 3.7 Å resolution structure (6KXW, deposited to the PDB on Sept 13, 2019) of human AQP7-and reported in preliminary form (Zhang et al, 2019)-differs from ours in several respects:…”

Section: Structural Analysiscontrasting

confidence: 68%

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Aquaporin-7: A Dynamic Aquaglyceroporin With Greater Water and Glycerol Permeability Than Its Bacterial Homolog GlpF

et al. 2020

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Xenopus oocytes expressing human aquaporin-7 (AQP7) exhibit greater osmotic water permeability and 3 H-glycerol uptake vs. those expressing the bacterial glycerol facilitator GlpF. AQP7-expressing oocytes exposed to increasing extracellular [glycerol] under isosmolal conditions exhibit increasing swelling rates, whereas GlpF-expressing oocytes do not swell at all. To provide a structural basis for these observed physiological differences, we performed X-ray crystallographic structure determination of AQP7 and molecular-dynamics simulations on AQP7 and GlpF. The structure reveals AQP7 tetramers containing two monomers with 3 glycerols, and two monomers with 2 glycerols in the pore. In contrast to GlpF, no glycerol is bound at the AQP7 selectivity filter (SF), comprising residues F74, G222, Y223, and R229. The AQP7 SF is resolved in its closed state because F74 blocks the passage of small solutes. Molecular dynamics simulations demonstrate that F74 undergoes large and rapid conformational changes, allowing glycerol molecules to permeate without orientational restriction. The more rigid GlpF imposes orientational constraints on glycerol molecules passing through the SF. Moreover, GlpF-W48 (analogous to AQP7-F74) undergoes rare but long-lasting conformational changes that block the pore to H 2 O and glycerol.

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Section: Structural Analysiscontrasting

confidence: 68%

“…A 3.7 Å resolution structure (6KXW, deposited to the PDB on Sept 13, 2019) of human AQP7—and reported in preliminary form ( Zhang et al, 2019 )—differs from ours in several respects:…”

Section: Discussioncontrasting

confidence: 58%

Aquaporin-7: A Dynamic Aquaglyceroporin With Greater Water and Glycerol Permeability Than Its Bacterial Homolog GlpF

et al. 2020

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“…Although it is unexpected to find a C2 symmetry on the tetrameric ring of hDERL1s, a higher oligomer with lower symmetry is precedented in other studies. For example, glycerol aquaporin AQP10 and AQP7 were reported to form a homotetramer, but both have slightly different conformations among the protomers in the tetramer ( 23 , 24 ). hDERL1 tetramer is primarily maintained by the interactions between loops 5 and 1 from neighboring protomers, and very limited interactions were identified on the TM helices between protomers ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The cryo-EM structure of an ERAD protein channel formed by tetrameric human Derlin-1

Rao

Yao

et al. 2021

Sci. Adv.

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Endoplasmic reticulum–associated degradation (ERAD) is a process directing misfolded proteins from the ER lumen and membrane to the degradation machinery in the cytosol. A key step in ERAD is the translocation of ER proteins to the cytosol. Derlins are essential for protein translocation in ERAD, but the mechanism remains unclear. Here, we solved the structure of human Derlin-1 by cryo–electron microscopy. The structure shows that Derlin-1 forms a homotetramer that encircles a large tunnel traversing the ER membrane. The tunnel has a diameter of about 12 to 15 angstroms, large enough to allow an α helix to pass through. The structure also shows a lateral gate within the membrane, providing access of transmembrane proteins to the tunnel, and thus, human Derlin-1 forms a protein channel for translocation of misfolded proteins. Our structure is different from the monomeric yeast Derlin structure previously reported, which forms a semichannel with another protein.

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Identification of V59L and A953G genotypes distribution in AQP7 and their association with glycerol in overweight/obese Malay patients

Masri,

Razali,

Abdul Rahman

et al. 2024

APJMBB

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One significant public health issue contributing to cardiovascular risk factors is obesity. Previous evidence suggested that abnormal glycerol metabolism and aquaporin 7 (AQP7) dysfunction in promoting glycerol influx and efflux from the adipose tissue are among the mechanisms involved in obesity. This pilot study aims to identify the genotype distribution of polymorphisms in the AQP7 gene (AQP7) and to find their association with plasma glycerol. A cross-sectional study was undertaken at Hospital Universiti Teknologi MARA (HUiTM) Sungai Buloh, Selangor, Malaysia, on 56 normal and 44 overweight/obese participants. Anthropometry data was collected from all participants. Blood samples were taken by venipuncture to measure plasma glycerol and subsequently, the genotypes of two SNPs in AQP7 (V59L rs4008659 and A953G rs2989924) were determined for both groups. The genotype distribution and allele frequencies of both SNPs in the AQP7 were established, and their association with plasma glycerol was estimated by logistic regression. Participants in the overweight/obese group had higher plasma glycerol (median = 0.78 mg/dL, Q1-Q3=0.47-1.42) than the normal group. V59L and A953G genotypes distribution between normal and overweight/obese groups showed no significant difference. Logistic regression analysis showed that participants with the A953G (rs2989924) TC genotype had a 71% decreased risk of developing abnormal plasma glycerol when factors such as age, gender, and waist-to-hip ratio (WHR) were controlled. No similar association was seen in the participants with the V59L (rs4008659) genotypes. This study highlighted the potential role of the A953G (rs2989924) TC genotype in reducing the risk of having impaired glycerol metabolism, reflecting its likely protective nature against obesity.

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The Structural Basis for Glycerol Permeation by human AQP7

Cited by 3 publications

References 34 publications

Aquaporin-7: A Dynamic Aquaglyceroporin With Greater Water and Glycerol Permeability Than Its Bacterial Homolog GlpF

Aquaporin-7: A Dynamic Aquaglyceroporin With Greater Water and Glycerol Permeability Than Its Bacterial Homolog GlpF

The cryo-EM structure of an ERAD protein channel formed by tetrameric human Derlin-1

Identification of V59L and A953G genotypes distribution in AQP7 and their association with glycerol in overweight/obese Malay patients

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