Structural Determinants of Oligomerization of the Aquaporin-4 Channel

Kitchen, Philip; Conner, Matthew T.; Bill, Roslyn M.; Conner, Alex C.

doi:10.1074/jbc.m115.694729

Cited by 30 publications

(38 citation statements)

References 42 publications

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“…Regarding structural features, loss of tetramerization does not affect the single channel permeability of AQP1, AQP4 and the aquaglyceroporin AQP3. These observations support the hypothesis that loop D-mediated inter-monomer interactions may control the formation of the signature quaternary structure of the family, but seems not to be necessary for trafficking to the plasma membrane (Kitchen et al 2016).…”

Section: Aqp Dynamics: Trafficking and Localizationsupporting

confidence: 83%

Plant and animal aquaporins crosstalk: what can be revealed from distinct perspectives

2017

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Aquaporins (AQPs) can be revisited from a distinct and complementary perspective: the outcome from analyzing them from both plant and animal studies. (1) The approach in the study. Diversity found in both kingdoms contrasts with the limited number of crystal structures determined within each group. While the structure of almost half of mammal AQPs was resolved, only a few were resolved in plants. Strikingly, the animal structures resolved are mainly derived from the AQP2-lineage, due to their important roles in water homeostasis regulation in humans. The difference could be attributed to the approach: relevance in animal research is emphasized on pathology and in consequence drug screening that can lead to potential inhibitors, enhancers and/or regulators. By contrast, studies on plants have been mainly focused on the physiological role that AQPs play in growth, development and stress tolerance. (2) The transport capacity. Besides the well-described AQPs with high water transport capacity, large amount of evidence confirms that certain plant AQPs can carry a large list of small solutes. So far, animal AQP list is more restricted. In both kingdoms, there is a great amount of evidence on gas transport, although there is still an unsolved controversy around gas translocation as well as the role of the central pore of the tetramer. (3) More roles than expected. We found it remarkable that the view of AQPs as specific channels has evolved first toward simple transporters to molecules that can experience conformational changes triggered by biochemical and/or mechanical signals, turning them also into signaling components and/or behave as osmosensor molecules.

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Section: Aqp Dynamics: Trafficking and Localizationsupporting

confidence: 83%

Plant and animal aquaporins crosstalk: what can be revealed from distinct perspectives

2017

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“…Despite clear clinical importance, little is known concerning AQP trafficking and higher order assembly in trypanosomes and specifically the impact of mutations on these properties. We found that TbAQP2 assembles into high molecular weight complexes that potentially resemble the quasi-arrays described for HsAQP4 [67–71]. Oligomerization correlates with bidirectional glycerol flow but also pentamidine sensitivity as C-terminal tagged forms form oligomers with low efficiency and have poor transport activity.…”

Section: Discussionmentioning

confidence: 87%

“…Consistent with this is that both TbAQP1 and TbAQP2 assemble into higher order complexes but TbAQP3 apparently does so less efficiently. Similarly, TbAQP1 and TbA have a long half-life (t 1/2 >4 h) and restricted subcellular localisation around the flagellar pocket, whereas TbAQP3 is comparatively short-lived (t 1/2 ∼1 h) and localises mainly to the cell body surface, suggesting a connection between oligomerisation, stability, subcellular localisation and transport activity [67,69–71]. Furthermore, replacement of TMD4 or 6 in TbAQP2 by TbAQP3 sequences (we were unable to generate TMD5 chimeras), as observed in clinically relevant chimeric AQP2-3, led to impaired oligomerisation, ER-retention and decreased stability, strengthening the correlation between oligomerisation, localisation and function.…”

Section: Discussionmentioning

confidence: 99%

Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance inTrypanosoma brucei

Quintana

Bueren-Calabuig

Zuccotto

et al. 2020

Preprint

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34Defining mode of action is vital for both developing new drugs and predicting 35 potential resistance mechanisms. African trypanosome pentamidine and 36 melarsoprol sensitivity is predominantly mediated by aquaglyceroporin 2 (TbAQP2), a 37 channel associated with water/glycerol transport. TbAQP2 is expressed at the flagellar 38 pocket membrane and chimerisation with TbAQP3 renders parasites resistant to both 39 drugs. Two models for how TbAQP2 mediates pentamidine sensitivity have emerged; 40 that TbAQP2 mediates pentamidine translocation or via binding to TbAQP2, with 41 subsequent endocytosis, but trafficking and regulation of TbAQPs is uncharacterised. 42We demonstrate that TbAQP2 is organised as a high order complex, is ubiquitylated 43 and transported to the lysosome. Unexpectedly, mutation of potential ubiquitin 44 conjugation sites, i.e. cytoplasmic lysine residues, reduced folding and tetramerization 45 efficiency and triggered ER retention. Moreover, TbAQP2/TbAQP3 chimerisation also 46 leads to impaired oligomerisation, mislocalisation, and increased turnover. These data 47suggest that TbAQP2 stability is highly sensitive to mutation and contributes towards 48 emergence of drug resistance. 49 50 Human African trypanosomiasis (HAT) is a neglected tropical disease affecting 52 sub-Saharan countries [1-4]. HAT progresses by two stages: a haemolymphatic 53 stage, in which the parasite successfully colonises the bloodstream, lymphatics, skin, 54 adipose tissue and organs and a meningoencephalic stage characterised by the 55 emergence of parasites in the central nervous system (CNS) [2,5]. Several drugs are 56 used to treat HAT; currently suramin and pentamidine are the drugs of choice for 57 treatment of the haemolymphatic stage of T. brucei rhodesiense and T. brucei 58 gambiense infections respectively, whereas melarsoprol, eflornithine or combined 59 nifurtimox-eflornithine (NECT) therapy are recommended for the meningoencephalic 60 stage [6,7]. 61 Two new drugs, fexinidazole and acoziborole, recently completed clinical trials 62 and opened a new front in HAT chemotherapy [8,9]. Drug development, successful 63 public health initiatives and active case-monitoring programs have all contributed to 64 the anticipated eradication of gambiense HAT as a major public health problem in the 65 coming decade [10]. However, vigilance and understanding of drug mechanisms and 66 possible resistance pathways remain essential to maintain this situation, and 67rhodesiense HAT cannot be eliminated in this way as it is highly zoonotic [11]. 68Genome-wide RNAi screens identified a number of genes associated with 69 pentamidine sensitivity that, together with evidence from melarsoprol-pentamidine 70 cross-resistance (MPXR), identified aquaglyceroporin 2 as the primary determinant for 71 drug-uptake [12,13], alongside lesser roles for the TbAT1/P2 aminopurine transporter 72 and the Low Affinity Pentamidine transporter LAPT1 [14]. 73 Aquaglyceroporins (AQPs) are an ancient family of multi-pass membrane 74 proteins, containing b...

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“…The role of tetramerization is still incompletely defined. However, recent evidence suggests it is a requisite of the regulatory mechanism [ 12 ]. Like most TM transporters, AQPs have evolved to become highly specific for their transport molecules.…”

Section: Introduction–human Aquaporinsmentioning

confidence: 99%

Aquaporins and Their Regulation after Spinal Cord Injury

Halsey

Conner

Bill

et al. 2018

Cells

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After injury to the spinal cord, edema contributes to the underlying detrimental pathophysiological outcomes that lead to worsening of function. Several related membrane proteins called aquaporins (AQPs) regulate water movement in fluid transporting tissues including the spinal cord. Within the cord, AQP1, 4 and 9 contribute to spinal cord injury (SCI)-induced edema. AQP1, 4 and 9 are expressed in a variety of cells including astrocytes, neurons, ependymal cells, and endothelial cells. This review discusses some of the recent findings of the involvement of AQP in SCI and highlights the need for further study of these proteins to develop effective therapies to counteract the negative effects of SCI-induced edema.

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Structural Determinants of Oligomerization of the Aquaporin-4 Channel

Cited by 30 publications

References 42 publications

Plant and animal aquaporins crosstalk: what can be revealed from distinct perspectives

Plant and animal aquaporins crosstalk: what can be revealed from distinct perspectives

Instability of aquaglyceroporin (AQP) 2 contributes to drug resistance inTrypanosoma brucei

Aquaporins and Their Regulation after Spinal Cord Injury

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