Energetic and Molecular Water Permeation Mechanisms of the Human Red Blood Cell Urea Transporter B

Azouzi, Slim; Guéroult, Marc; Ripoche, Pierre; Genetet, Sandrine; Colin, Yves; Kim, Caroline Le Van; Etchebest, Catherine; Mouro-Chanteloup, Isabelle

doi:10.1371/journal.pone.0082338

Cited by 30 publications

(31 citation statements)

References 65 publications

(104 reference statements)

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“…Recent estimates of the rate of water permeation through UT-B are similar to those measured for aquaporins (Azouzi et al 2013). Given the similarities between the architecture of the aquaporin and UT pores discussed above, this result is not entirely surprising.…”

Section: 4 Interactions With Ligands and The Structural Basis Of supporting

confidence: 57%

“…Given the similarities between the architecture of the aquaporin and UT pores discussed above, this result is not entirely surprising. Molecular dynamics simulations of water permeation through a homology model of human UT-B, based on the bovine UT-B structure, suggest that the magnitude of the energy barrier for water permeation is similar to that observed for aquaporins (Azouzi et al 2013). The observation that UT-B is an efficient water channel raises the question of how protons are excluded from leaking through the pore.…”

Section: 4 Interactions With Ligands and The Structural Basis Of mentioning

confidence: 67%

“…In contrast, the UT selectivity filter lacks any positively charged side chains, and the orientations of the two pore helices are reversed relative to aquaporins, leading to a negative potential at the S m site rather than a positive one. Interestingly, molecular dynamics simulations predict that water permeating through UT-B undergoes a reversal of the orientation of its dipole moment correlated to passage through the S m site (Azouzi et al 2013). A similar change in orientation was predicted by molecular dynamics simulations in aquaporins (de Groot and Grubmuller 2001; Tajkhorshid et al 2002), and recently gained experimental support from an ultra-high crystal structure of a yeast aquaporin (Kosinska Eriksson et al 2013).…”

Section: 4 Interactions With Ligands and The Structural Basis Of mentioning

confidence: 99%

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Structure of Urea Transporters

Levin

Zhou

2014

Subcellular Biochemistry

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Members of the urea transporter (UT) family mediate rapid, selective transport of urea down its concentration gradient. To date, crystal structures of two evolutionarily distant UTs have been solved. These structures reveal a common UT fold involving two structurally homologous domains that encircle a continuous membrane-spanning pore, and indicate that UTs transport urea via a channel-like mechanism. Examination of the conserved architecture of the pore, combined with crystal structures of ligand-bound proteins, molecular dynamics simulations, and functional data on permeation and inhibition by a broad range of urea analogs and other small molecules, provides insight into the structural basis of urea permeation and selectivity.

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Section: 4 Interactions With Ligands and The Structural Basis Of supporting

confidence: 57%

Section: 4 Interactions With Ligands and The Structural Basis Of mentioning

confidence: 67%

Section: 4 Interactions With Ligands and The Structural Basis Of mentioning

confidence: 99%

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Structure of Urea Transporters

Levin

Zhou

2014

Subcellular Biochemistry

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“…Water, HCO3 − /Cl − and ammonia permeabilities of ghosts from human erythrocyte variants were determined by using stopped-flow spectrophotometer (SFM74, BioLogic, Grenoble, France) as previously described (Azouzi , et al 2013, Frumence , et al 2013, Genetet , et al 2012). …”

Section: Methodsmentioning

confidence: 99%

The human Kell blood group binds the erythroid 4.1R protein: new insights into the 4.1R-dependent red cell membrane complex

et al. 2015

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Summary Protein 4.1R plays an important role in maintaining the mechanical properties of the erythrocyte membrane. We analysed the expression of Kell blood group protein in erythrocytes from a patient with hereditary elliptocytosis associated with complete 4.1R deficiency (4.1(−) HE). Flow cytometry and Western blot analyses revealed a severe reduction of Kell. In vitro pull down and co-immunoprecipitation experiments from erythrocyte membranes showed a direct interaction between Kell and 4.1R. Using different recombinant domains of 4.1R and the cytoplasmic domain of Kell, we demonstrated that the R46R motif in the juxta-membrane region of Kell binds to lobe B of the 4.1R FERM domain. We also observed that 4.1R deficiency is associated with a reduction of XK and DARC (also termed ACKR1) proteins, the absence of the glycosylated form of the urea transporter B and a slight decrease of band 3. The functional alteration of the 4.1(−) HE erythrocyte membranes was also determined by measuring various transport activities. We documented a slower rate of HCO3−/Cl− exchange, but normal water and ammonia transport across erythrocyte membrane in the absence of 4.1. These findings provide novel insights into the structural organization of blood group antigen proteins into the 4.1R complex of the human red cell membrane.

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“…26 Interestingly, despite the narrow and desolvating S m constriction site, UT-B can conduct water, whereas the UT-A isoforms cannot. 33–35 …”

Section: Ut Proteinsmentioning

confidence: 99%

Urea transporter proteins as targets for small-molecule diuretics

Esteva‐Font

Anderson

2014

Nat Rev Nephrol

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Conventional diuretics such as furosemide and thiazides target salt transporters in kidney tubules, but urea transporters (UTs) have emerged as alternative targets. UTs are a family of transmembrane channels expressed in a variety of mammalian tissues, in particular the kidney. UT knockout mice and humans with UT mutations exhibit reduced maximal urinary osmolality, demonstrating that UTs are necessary for the concentration of urine. Small-molecule screening has identified potent and selective inhibitors of UT-A, the UT protein expressed in renal tubule epithelial cells, and UT-B, the UT protein expressed in vasa recta endothelial cells. Data from UT knockout mice and from rodents administered UT inhibitors support the diuretic action of UT inhibition. The kidney-specific expression of UT-A1, together with high selectivity of the small-molecule inhibitors, means that off-target effects of such small-molecule drugs should be minimal. This Review summarizes the structure, expression and function of UTs, and looks at the evidence supporting the validity of UTs as targets for the development of salt-sparing diuretics with a unique mechanism of action. UT-targeted inhibitors may be useful alone or in combination with conventional diuretics for therapy of various oedemas and hyponatraemias, potentially including those refractory to treatment with current diuretics.

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Energetic and Molecular Water Permeation Mechanisms of the Human Red Blood Cell Urea Transporter B

Cited by 30 publications

References 65 publications

Structure of Urea Transporters

Structure of Urea Transporters

The human Kell blood group binds the erythroid 4.1R protein: new insights into the 4.1R-dependent red cell membrane complex

Urea transporter proteins as targets for small-molecule diuretics

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