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From Structure to Disease: the Evolving Tale of Aquaporin Biology

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From Structure to Disease: the Evolving Tale of Aquaporin Biology REVIEWS FROM STRUCTURE TO DISEASE: THE EVOLVING TALE OF AQUAPORIN BIOLOGY Landon S. King, David Kozono and Peter Agre Abstract | Our understanding of the movement of water through cell membranes has been greatly advanced by the discovery of a family of water-specific, membrane-channel proteins — the aquaporins. These proteins are present in organisms at all levels of life, and their unique permeability characteristics and distribution in numerous tissues indicate diverse roles in the regulation of water homeostasis. The recognition of aquaporins has stimulated a reconsideration of membrane water permeability by investigators across a wide range of disciplines. The existence of proteins that form water-specific groups (FIG. 1) on the basis of their permeability char- membrane channels was postulated for several decades, acteristics, which generally coincide with specific largely on the basis of biophysical measurements of amino-acid-sequence patterns. Most members of the membrane permeability in red blood cells and in first group (aquaporins) are only permeated by water, epithelial cells of the renal proximal tubule1.However, and this group includes AQP0, AQP1, AQP2, AQP4, the identity of such channels remained unknown until AQP5, AQP6 and AQP8.AQP6 and AQP8 are in this approximately 12 years ago, when the serendipitous dis- group on the basis of sequence analysis, although covery of a red-blood-cell protein led to the description AQP6 is permeated by anions6 and AQP8 might be of aquaporin-1 (AQP1) as the first molecular water permeated by water and urea7,8.Members of the sec- channel2.Water can be transported to varying degrees ond group (aquaglyceroporins), which includes AQP3, by other membrane proteins, for example, the Na+/glu- AQP7, AQP9 and AQP10,are permeated by water to cose co-transporter3.However,recognition of the varying degrees, but are also permeated by other small unique properties of the aquaporins led to a paradigm solutes, in particular, glycerol. The bacterium shift in our consideration of membrane permeability: it Escherichia coli provides a model for this categoriza- is now known that water transport across the mem- tion, as it contains two aquaporin homologues — brane can be regulated independently of solute trans- AqpZ,which is a water-permeable channel, and GlpF, port. Recent reports from laboratories around the which is a glycerol transporter (FIG. 1). Department of Medicine, world have advanced our understanding of aquaporin Why do we need so many aquaporins? The answer Division of Pulmonary and biology, from the structural determinants of channel probably derives from the diverse requirements in dif- Critical Care Medicine, permeability to the assignment of their physiological ferent cells and organs for the regulation of water and the Department of function in different organs. These advances are the homeostasis. Aquaporins in the collecting duct of the Biological Chemistry, The Johns Hopkins focus of this review. kidney, capillaries in the lung and secretory cells in sali- University School of vary glands (see below) are all capable of high rates of Medicine, 5501 Hopkins The aquaporin protein family water transport. However, across the aquaporin family, Bayview Circle, Baltimore, Eleven mammalian aquaporins have been reported so differences have been identified in the transcriptional Maryland 21224, USA. far4,5 (TABLE 1).Each has a unique cellular and subcellu- regulation of the genes, as well as in the post-transla- Correspondence to L.S.K. e-mail: [email protected] lar distribution, with little overlap between homo- tional modification, stability and polarized distribution doi:10.1038/nrm1469 logues. The aquaporin family can be divided into two of the proteins. As noted above, it is also evident that the NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 5 | SEPTEMBER 2004 | 687 © 2004 Nature Publishing Group REVIEWS Table 1 | Permeability characteristics and predominant distribution for the known mammalian aquaporin homologues Aquaporin Permeability Tissue distribution Subcellular distribution* AQP0 Water (low) Lens Plasma membrane AQP1 Water (high) Red blood cell, kidney, lung, vascular endothelium, brain, eye Plasma membrane AQP2 Water (high) Kidney, vas deferens Apical plasma membrane, intracellular vesicles AQP3 Water (high), glycerol (high), Kidney, skin, lung, eye, colon Basolateral plasma membrane urea (moderate) AQP4 Water (high) Brain, muscle, kidney, lung, stomach, small intestine Basolateral plasma membrane AQP5 Water (high) Salivary gland, lacrimal gland, sweat gland, lung, cornea Apical plasma membrane – – AQP6 Water (low), anions (NO3 > Cl )Kidney Intracellular vesicles AQP7 Water (high), glycerol (high), Adipose tissue, kidney, testis Plasma membrane urea (high), arsenite AQP8‡ Water (high) Testis, kidney, liver, pancreas, small intestine, colon Plasma membrane, intracellular vesicles AQP9 Water (low), glycerol (high), Liver, leukocytes, brain, testis Plasma membrane urea (high), arsenite AQP10 Water (low), glycerol (high), urea (high) Small intestine Intracellular vesicles *Homologues that are present primarily in either the apical or basolateral membrane are noted as residing in one of these membranes, whereas homologues that are present in both of these membranes are described as having a plasma-membrane distribution. ‡AQP8 might be permeated by water and urea. AQP, aquaporin. permeability characteristics differ among some mem- analysis of residues around the conserved NPA motifs bers of the family. The complexity in the regulation of led to predictions of an ‘hourglass’ structure, with two expression, membrane targeting and permeability loops — the intracellular loop B and the extracellular necessitates the existence of more than just a single loop E — folding into the membrane to form the water-channel gene. Certainly, we must still expect to pore12 (FIG. 2a).Several recent structural studies — find new and surprising physiological functions for the which include cryo-electron microscopy of human aquaporins that require complex patterns of expression red-blood-cell AQP1 to 3.8-Å resolution13,14 and X-ray and regulation. crystal structures of GlpF15 and bovine AQP1 (REF. 16) to 2.2-Å and 2.1-Å resolution, respectively — have The unique aquaporin structure confirmed the predicted hourglass structure. In addi- Biochemical analyses of AQP1 revealed that the 28-kDa tion, these studies have greatly advanced our under- polypeptide that was evident on immunoblots repre- standing of the unique permeability characteristics of sented the monomeric form of the protein, but that the aquaporins (see below). AQP1 (as well as other aquaporins) is present as a tetramer in the cell membrane9. FREEZE–FRACTURE studies Tetramer formation.Aquaporins are present in the mem- also highlighted a tetrameric arrangement of the brane as tetramers, but, unlike ion channels, the channel protein10.Recent studies have greatly enhanced our for water permeability does not reside at the fourfold axis insights into the details of the aquaporin structure that (the centre of the tetramer). Instead, each monomer direct this tetrameric arrangement, as well as into those contains a channel12 (FIG. 2b).Structural studies have features that dictate the permeability characteristics of provided insights into the apparent requirement for the water channel. tetramer formation9.The helices of each AQP1 monomer that are positioned on the outside face of Monomer structure.The signature sequence motif of the tetramer are hydrophobic, whereas those that are the aquaporins is the three-amino-acid sequence NPA placed towards the centre of the tetramer are (Asn-Pro-Ala). One NPA motif is found in the amino- hydrophilic17. terminal half of each monomer, and a second NPA motif is found in the carboxy-terminal half1 (FIG. 2a). Channel selectivity and gating.Structural studies also When their amino termini are aligned, the overall per- revealed that the restriction of AQP1 permeability to + FREEZE–FRACTURE centage sequence identity among the aquaporin-fam- water — excluding even hydronium (H3O ) ions — A technique that allows the ily members is ~25–40%. However, it is much higher arises from two principal mechanisms16–19. First, the examination of membrane for the sequences that flank each of the NPA motifs. In channels narrow to a diameter of 2.8 Å approximately proteins by first freezing and then fracturing a tissue to addition to the similarity between the different aqua- 8Å above the centre of the bilayer, which physically lim- separate the inner and outer porins, the amino- and carboxy-terminal halves of its the size of molecules that can pass through them. A leaflets of the membrane bilayer. AQP1 are related by their sequence, although these highly conserved arginine residue provides a fixed posi- This technique can be halves are oriented in opposite directions across the tive charge at this constriction site in each channel. The particularly useful for the membrane bilayer (FIG. 2a).Hydropathy analysis of narrowest part of an E. coli GlpF channel is ~1 Å wider examination of integral membrane proteins and cell AQP1 indicated the presence of six transmembrane than in AQP1, and this increased diameter is sufficient junctions. helices in each monomer11.In addition, mutational to allow glycerol to pass through GlpF channels. Such 688 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/molcellbio © 2004 Nature Publishing Group REVIEWS membrane-junction formation stabilizes AQP0 in a Aquaporins AQP4 AQP5 21 AQP2 closed conformation
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