Aquaporin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Crystallographic structure of the aquaporin 1 (AQP1) channel (PDB: 1J4N​).

Aquaporin, are integral membrane proteins from a larger family of major intrinsic proteins (MIP) that form pores in the membrane of biological cells.[1]

Genetic defects involving aquaporin genes have been associated with several human diseases.[2][3] The 2003 Nobel Prize in Chemistry was awarded to Peter Agre for the discovery of aquaporins[4] and jointly to Roderick MacKinnon for his work on the structure and mechanism of potassium channels.[5]

Function

Aquaporins selectively conduct water molecules in and out, while preventing the passage of ions and other solutes. Also known as water channels, aquaporins are membrane pore proteins. Aquaporins are commonly composed of four (typically) identical subunit proteins in mammals, with each monomer acting as a water channel.[6]

Water molecules traverse through the pore of the channel in single file. The presence of water channels increases membrane permeability to water.

Many human cell types express them, as do certain bacteria and many other organisms, such as plants for which it is essential for the water transport system.[7]

Discovery

In most cells, water moves in and out by osmosis through the lipid component of cell membranes. Due to the relatively high water permeability of some epithelial cells it was long suspected that some additional mechanism for water transport across membranes must exist, but it was not until the discovery of the first aquaporin, ‘aquaporin-1’ (originally known as CHIP), was reported by Peter Agre, then of Johns Hopkins University and now a professor and administrator at Duke University. The discovery of this first aquaporin took place in 1992.[8]

The pioneering discoveries and research on water channels by Agre and his colleagues resulted in the presentation of a Nobel Prize in Chemistry to Agre in 2003.[5] In 1999, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure of an aquaporin, viz. aquaporin-1.[9] Further studies using supercomputer simulations have identified the pathway of water as it moves through the channel and demonstrated how a pore can allow water to pass without the passage of small solutes.[10]

However the first report of protein mediated water transport through membranes was by Gheorghe Benga in 1986.[11][12] This publication which preceded Agre"s first publication on water membrane transport proteins has led to a controversy that Benga's work was neither adequately recognized by Agre nor the Nobel Prize Committee.[13]

Structure

Schematic diagram of the 2D structure of aquaporin 1 (AQP1) depicting the six transmembrane alpha-helices and the five interhelical loop regions A-E.
The 3D structure of aquaporin highlighting the 'hourglass' shaped water channel which cuts through the center of the protein.

Aquaporins are made up of six transmembrane α-helices arranged in a right-handed bundle, with the amino and the carboxyl termini located on the cytoplasmic surface of the membrane.[6][14] The amino and carboxyl halves of the sequence show similarity to each other, in what appears to be a tandem repeat. Some researches believe that this results from an early evolution event which saw the duplication of the half sized gene. There are also five interhelical loop regions (A – E) that form the extracellular and cytoplasmic vestibules. Loops B and E are hydrophobic loops which contain the highly, although not completely conserved Asn-Pro-Ala (NPA) motif, which overlap the middle of the lipid bilayer of the membrane forming a 3-D 'hourglass' structure where the water flows through. This overlap forms one of the two well-known channel constriction sites in the peptide, the NPA motif and a second and usually narrower constriction known as 'selectivity filter' or ar/R selectivity filter.

Aquaporins form tetramers in the cell membrane, and facilitate the transport of water and, in some cases, other small uncharged solutes, such as glycerol, CO2, ammonia and urea across the membrane depending on the size of the pore. The different aquaporins contain differences in their peptide sequence which allows for the size of the pore in the protein to differ between aquaporins. The resultant size of the pore directly affects what molecules are able to pass through the pore, with small pore sizes only allowing small molecules like water to pass through the pore. However, the water pores are completely impermeable to charged species, such as protons, a property critical for the conservation of membrane's electrochemical potential.

NPA motif

Using computer simulations, it has been suggested that the orientation of the water molecules moving through the channel assures that only water passes between cells, due to the formation of a single line of water molecules. The water molecules move through the narrow channel by orienting themselves in the local electrical field formed by the atoms of the channel wall. Upon entering, the water molecules face with their oxygen atom down the channel. Midstream, they reverse orientation, facing with the oxygen atom up. This rotation of the water molecules in the pore is caused by the interaction of hydrogen bonds between the oxygen of the water molecule and the asparagines in the two NPA motifs. While passing through the channel, the single-file chain of water molecules streams through, always entering face down and leaving face up. The strictly opposite orientations of the water molecules keep them from conducting protons via the Grotthuss mechanism, while still permitting a fast flux of water molecules.[15]

ar/R selectivity filter

Schematic depiction of water movement through the narrow selectivity filter of the aquaporin channel.

The ar/R (aromatic/arginine) selectivity filter is a cluster of amino acids that help bind to water molecules and exclude other molecules that may try to enter the pore. It is the mechanism by which the aquaporin is able to selectively bind water molecules (hence allowing them through) and prevent other molecules from entering. The ar/P filter is a tetrad that is formed by two amino acid residues from helices 2 (H2) and 5 (H5) and two residues from loop E (LE1 and LE2), found on either side of the NPA motif. The ar/R region is usually found towards the extracellular vestibule, approximately 8 Å above the NPA motif and is often the narrowest part of the pore. The narrow pore acts to weaken the hydrogen bonds between the water molecules allowing the water to interact with the positively charged arginine, which also acts as a proton filter for the pore.

Aquaporins in mammals

There are thirteen known types of aquaporins in mammals, and six of these are located in the kidney,[16] but the existence of many more is suspected. The most studied aquaporins are:

Water crosses the cell membrane by either diffusing through the phospholipid bilayer or by passing through special water channels. Most aquaporins appear to be exclusive water channels that will not allow permeation of ions or other small molecules. Some aquaporins - known as aquaglyceroporins - transport water plus glycerol and a few other small molecules.

Comparison

Type Location[17] Function[17]
Aquaporin 1 Water reabsorption
Aquaporin 2 Water reabsorption in response to ADH
Aquaporin 3 Water reabsorption
Aquaporin 4 Water reabsorption

Aquaporins in plants

In plants water is taken up from the soil through the roots, where it passes from the cortex into the vascular tissues. There are two routes for water to flow in these tissues, known as the; apoplastic and symplastic pathways. The presence of aquaporins in the cell membranes seems to serve to facilitate the transcellular symplastic pathway for water transport. When plant roots are exposed to mercuric chloride, which is known to inhibit aquaporins, the flow of water is greatly reduced while the flow of ions is not, supporting the view that there exists a mechanism for water transport independent of the transport of ions; aquaporins.

Aquaporins in plants are separated into four main homologous subfamilies, or groups:[18]

  • Plasma membrane Intrinsic Protein (PIP)
  • Tonoplast Intrinsic Protein (TIP)[19]
  • Nodulin-26 like Intrinsic Protein (NIP)[20]
  • Small basic Intrinsic Protein (SIP)[21]

These four subfamilies have continued to be broken up into smaller evolutionary subgroups that are directly related to their DNA sequence specificity. PIPs cluster into two subgroups, PIP1 and PIP2, whilst TIPs cluster into 5 subgroups, TIP1, TIP2, TIP3, TIP4 and TIP5. Each subgroup is again split up into isoforms e.g. PIP1;1, PIP1;2.

The silencing of plant aquaporins has been linked to pore plant growth and even death of the plant.

Gating of Plant Aquaporins

The gating of aquaporins is carried out to stop the flow of water through the pore of the protein. This may be carried out for a number of reasons, for example plant contains low amounts of cellular water due to drought.[22] The gating of an aquaporin is carried out by an interaction between a gating mechanism and the aquaporin which causes a 3D change in the protein so that it blocks the pore and thus disallows the flow of water through the pore. In plants it has been seen that there are at least two forms of aquaporin gating. These are gating by the dephosphorylation of certain serine residues, which has been linked as a response to drought, and the protonation of specific histidine residues in response to flooding. The phosphorylation of an aquaporin has also been linked to the opening and closing of a plant in response to temperature.

PIPs

Plasma membrane intrinsic proteins are found, as their name suggests in the plasma membrane of plant cells.[23] There are two PIP subgroups, PIP1 and PIP2, due to the distinct differences in their peptide sequence. PIP1s commonly have lower water channel activity than PIP2s although it is not understood why. Also not understood, but the water channel activity of PIP1s has been seen to increase when in the tetramer form with PIP2s.

Aquaporins and disease

There have been two clear examples of diseases identified as resulting from mutations in aquaporins:

A small number of people have been identified with severe or total deficiency in aquaporin-1. Interestingly, they are generally healthy, but exhibit a defect in the ability to concentrate solutes in the urine and to conserve water when deprived of drinking water. Mice with targeted deletions in aquaporin-1 also exhibit a deficiency in water conservation due to an inability to concentrate solutes in the kidney medulla by countercurrent multiplication.

In addition to its role in genetically determined nephrogenic diabetes insipidus, aquaporins also play a key role in acquired forms of nephrogenic diabetes insipidus (disorders that cause increased urine production).[26] Acquired nephrogenic diabetes insipidus can result from impaired regulation of aquaporin-2 due to administration of lithium salts (as a treatment for bipolar disorder), low potassium concentrations in the blood (hypokalemia), high calcium concentrations in the blood (hypercalcemia), or a chronically high intake of water beyond the normal requirements (e.g. due to excessive habitual intake of bottled water or coffee).

Finally, it has been found that autoimmune reactions against aquaporin 4 produce Devic's disease.[27]

References

  1. ↑ Agre P (2006). "The aquaporin water channels". Proc Am Thorac Soc. 3 (1): 5–13. doi:10.1513/pats.200510-109JH. PMID 16493146.
  2. ↑ Agre P, Kozono D (2003). "Aquaporin water channels: molecular mechanisms for human diseases". FEBS Lett. 555 (1): 72–8. doi:10.1016/S0014-5793(03)01083-4. PMID 14630322.
  3. ↑ Schrier RW (2007). "Aquaporin-related disorders of water homeostasis". Drug News Perspect. 20 (7): 447–53. doi:10.1358/dnp.2007.20.7.1138161. PMID 17992267.
  4. ↑ Knepper MA, Nielsen S (2004). "Peter Agre, 2003 Nobel Prize winner in chemistry". J. Am. Soc. Nephrol. 15 (4): 1093–5. doi:10.1097/01.ASN.0000118814.47663.7D. PMID 15034115.
  5. ↑ 5.0 5.1 "The Nobel Prize in Chemistry 2003". Nobel Foundation. Retrieved 2008-01-23.
  6. ↑ 6.0 6.1 Gonen T, Walz T (2006). "The structure of aquaporins". Q. Rev. Biophys. 39 (4): 361–96. doi:10.1017/S0033583506004458. PMID 17156589.
  7. ↑ Kruse E, Uehlein N, Kaldenhoff R (2006). "The aquaporins". Genome Biol. 7 (2): 206. doi:10.1186/gb-2006-7-2-206. PMID 16522221.
  8. ↑ Agre P, Preston GM, Smith BL, Jung JS, Raina S, Moon C, Guggino WB, Nielsen S (1993). "Aquaporin CHIP: the archetypal molecular water channel". Am. J. Physiol. 265 (4 Pt 2): F463–76. PMID 7694481.
  9. ↑ Mitsuoka K, Murata K, Walz T, Hirai T, Agre P, Heymann JB, Engel A, Fujiyoshi Y (1999). "The structure of aquaporin-1 at 4.5-A resolution reveals short alpha-helices in the center of the monomer". J. Struct. Biol. 128 (1): 34–43. doi:10.1006/jsbi.1999.4177. PMID 10600556.
  10. ↑ de Groot BL, Grubmüller H (2005). "The dynamics and energetics of water permeation and proton exclusion in aquaporins". Curr. Opin. Struct. Biol. 15 (2): 176–83. doi:10.1016/j.sbi.2005.02.003. PMID 15837176.
  11. ↑ Benga G, Popescu O, Pop VI, Holmes RP (1986). "p-(Chloromercuri)benzenesulfonate binding by membrane proteins and the inhibition of water transport in human erythrocytes". Biochemistry. 25 (7): 1535–8. doi:10.1021/bi00355a011. PMID 3011064.
  12. ↑ Kuchel PW (2006). "The story of the discovery of aquaporins: convergent evolution of ideas--but who got there first?". Cell. Mol. Biol. (Noisy-le-grand). 52 (7): 2–5. PMID 17543213.
  13. ↑ G Benga. "Gheorghe Benga". Ad Astra - Online project for the Romanian Scientific Community. Retrieved 2008-04-05.
  14. ↑ Fu D, Lu M (2007). "The structural basis of water permeation and proton exclusion in aquaporins". Mol. Membr. Biol. 24 (5–6): 366–74. doi:10.1080/09687680701446965. PMID 17710641.
  15. ↑ Tajkhorshid E, Nollert P, Jensen MØ, Miercke LJ, O'Connell J, Stroud RM, Schulten K (2002). "Control of the selectivity of the aquaporin water channel family by global orientational tuning". Science. 296 (5567): 525–30. doi:10.1126/science.1067778. PMID 11964478.
  16. ↑ Nielsen S, Frøkiaer J, Marples D, Kwon TH, Agre P, Knepper MA (2002). "Aquaporins in the kidney: from molecules to medicine". Physiol. Rev. 82 (1): 205–44. doi:10.1152/physrev.00024.2001. PMID 11773613.
  17. ↑ 17.0 17.1 Unless else specified in table boxes, then ref is: Walter F., PhD. Boron. Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 842
  18. ↑ Kaldenhoff R, Bertl A, Otto B, Moshelion M, Uehlein N (2007). "Characterization of plant aquaporins". Meth. Enzymol. 428: 505–31. doi:10.1016/S0076-6879(07)28028-0. PMID 17875436.
  19. ↑ Maeshima M (2001). "TONOPLAST TRANSPORTERS: Organization and Function". Annu Rev Plant Physiol Plant Mol Biol. 52: 469–497. doi:10.1146/annurev.arplant.52.1.469. PMID 11337406.
  20. ↑ Wallace IS, Choi WG, Roberts DM (2006). "The structure, function and regulation of the nodulin 26-like intrinsic protein family of plant aquaglyceroporins". Biochim. Biophys. Acta. 1758 (8): 1165–75. doi:10.1016/j.bbamem.2006.03.024. PMID 16716251.
  21. ↑ Johanson U, Gustavsson S (2002). "A new subfamily of major intrinsic proteins in plants". Mol. Biol. Evol. 19 (4): 456–61. PMID 11919287.
  22. ↑ Kaldenhoff R, Fischer M (2006). "Aquaporins in plants". Acta Physiol (Oxf). 187 (1–2): 169–76. doi:10.1111/j.1748-1716.2006.01563.x. PMID 16734753.
  23. ↑ Kammerloher W, Fischer U, Piechottka GP, Schäffner AR (1994). "Water channels in the plant plasma membrane cloned by immunoselection from a mammalian expression system". Plant J. 6 (2): 187–99. doi:0.1111/j.1748-1716.2006.01563.x Check |doi= value (help). PMID 7920711.
  24. ↑ Bichet DG (2006). "Nephrogenic diabetes insipidus". Adv Chronic Kidney Dis. 13 (2): 96–104. doi:10.1053/j.ackd.2006.01.006. PMID 16580609.
  25. ↑ Okamura T, Miyoshi I, Takahashi K, Mototani Y, Ishigaki S, Kon Y, Kasai N (2003). "Bilateral congenital cataracts result from a gain-of-function mutation in the gene for aquaporin-0 in mice". Genomics. 81 (4): 361–8. doi:10.1016/S0888-7543(03)00029-6. PMID 12676560.
  26. ↑ Khanna A (2006). "Acquired nephrogenic diabetes insipidus". Semin. Nephrol. 26 (3): 244–8. doi:10.1016/j.semnephrol.2006.03.004. PMID 16713497.
  27. ↑ Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005). "IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel". J. Exp. Med. 202 (4): 473–7. doi:10.1084/jem.20050304. PMID 16087714.

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