Mechanism of Aquaporin-4's Fast and Highly Selective Water Conduction and Proton Exclusion

Tani, Kazuhide; Mitsuma, Tadanori; Hiroaki, Yoko; Kamegawa, Akiko; Nishikawa, Kyoji; Tanimura, Yukihiro; Fujiyoshi, Yoshinori

doi:10.1016/j.jmb.2009.04.049

Cited by 115 publications

(118 citation statements)

References 54 publications

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“…There are two isoforms of AQP4 with AQP4-M1 (323 aa) having a 22 amino acids longer N-terminus than AQP4-M23 (301 aa) (14)(15)(16). High-resolution crystal structures of AQP4 showed that the asparagine of each NPA motif forms hydrogen bonds to a water molecule in the center of the channel, which is different from AQP1 where two asparagines from both NPA motifs form hydrogen bonds to one water molecule (17)(18)(19). Some other studies showed different protein folding pathways between AQP4 and AQP1 during biogenesis (20,21).…”

Section: Introductionmentioning

confidence: 99%

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

Guan

et al. 2010

IUBMB Life

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SummaryThe two highly conserved NPA motifs (asparagine-prolinealanine, NPA) are the most important structural domains that play a crucial role in water-selective permeation in aquaporin water channels. However, the functions of NPA motifs in aquaporin (AQP) biogenesis remain largely unknown. Few AQP members with variations in NPA motifs such as AQP11 and AQP12 do not express in the plasma membrane, suggesting an important role of NPA motifs in AQP plasma membrane targeting. In this study, we examined the role of the two NPA motifs in AQP4 plasma membrane targeting by mutagenesis. We constructed a series of AQP4 mutants with NPA deletions or single amino acid substitutions in AQP4-M1 and AQP4-M23 isoforms and analyzed their expression patterns in transiently transfected FRT and COS-7 cells. Western blot analysis showed similar protein bands of all the AQP4 mutants and the wild-type AQP4. AQP4 immunofluorescence indicated that deletion of one or both NPA motifs resulted in defective plasma membrane targeting, with apparent retention in endoplasmic reticulum (ER). The A99T mutant mimicking AQP12 results in ER retention, whereas the A99C mutant mimicking AQP11 expresses normally in plasma membrane. Furthermore, the AQP4-M1 but not the M23 isoform with P98A substitution in the first NPA motif can target to the plasma membrane, indicating an interaction of Nterminal sequence of AQP4-M1 with the first NPA motif. These results suggest that NPA motifs play a key role in plasma membrane expression of AQP4 but are not involved in AQP4 protein synthesis and degradation. The NPA motifs may interact with other structural domains in the regulation of membrane trafficking during aquaporin biogenesis.

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Section: Introductionmentioning

confidence: 99%

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

Guan

et al. 2010

IUBMB Life

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“…In orthodox aquaporins, selective water permeability is determined by three specializations (2,(249)(250)(251). First, the narrowest constriction of each monomer, located close to the extracellular entrance, has a diameter of ~2.8 Å, identical to the diameter of a water molecule (252).…”

Section: Aquaporinsmentioning

confidence: 99%

“…First, the narrowest constriction of each monomer, located close to the extracellular entrance, has a diameter of ~2.8 Å, identical to the diameter of a water molecule (252). Second, this constriction site contains a positively charged arginine site that serves to block the entrance of protonated water and cations (251). Third, positively charged dipoles near the center of the channel cause formation of hydrogen bonds, which reorient the water molecules in the two halves of the channel and prevent proton flow (251).…”

Section: Aquaporinsmentioning

confidence: 99%

“…Second, this constriction site contains a positively charged arginine site that serves to block the entrance of protonated water and cations (251). Third, positively charged dipoles near the center of the channel cause formation of hydrogen bonds, which reorient the water molecules in the two halves of the channel and prevent proton flow (251). Despite the strict water selectivity, it has been shown that the central pore of some orthodox aquaporins is capable of transporting ions and gases, including O 2 and CO 2 and nitric oxide (253)(254)(255).…”

Section: Aquaporinsmentioning

confidence: 99%

“…Freeze fracture immunogold labeling has revealed that AQP4 tetramers are organized into specialized square structures referred to as orthogonal arrays of particles (square arrays) in astrocytic membranes (308). The size of these structures is determined by the ratio of the isoforms M1 and M23, as the latter is critical to stabilize the structure (251,308). The function of this organization remains unknown, but could potentially secure a very high capacity for water transport across the endfoot membrane (21).…”

Section: Distribution Of Aqp4 In the Brainmentioning

confidence: 99%

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Cryo‐EM in the Study of Membrane Transport Proteins

Kim

Johnson

Schmidt-Krey

2012

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Electron cryomicroscopy (cryo-EM) has evolved as a widely used approach to understand a range of structure-function questions, particularly of membrane proteins. Studies by both electron crystallography and single particle analysis have provided a wealth of information on membrane transport proteins. Cryo-EM methods with an emphasis on electron crystallography, which has yielded the most membrane transport protein structural information of any of the cryo-EM techniques, are described here. Two-dimensional crystallization approaches are outlined, as well as advances in cryo-EM specimen preparation, data collection, and image processing. Examples of membrane transport protein structure described serve to illustrate some of the advances in both structural understanding and methods. Further examples outline impressive results that were obtained by a combination of electron crystallography and X-ray crystallography as well as additional complementary methods.

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Mechanism of Aquaporin-4's Fast and Highly Selective Water Conduction and Proton Exclusion

Cited by 115 publications

References 54 publications

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

NPA motifs play a key role in plasma membrane targeting of aquaporin‐4

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

Cryo‐EM in the Study of Membrane Transport Proteins

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