Aquaporin-1
AquaporinsAquaporin-1 (AQP1) was first discovered in human red blood cell membranes by Gheorghe Benga's research group in 1986.[1] However, it was only known to be a novel protein and its function was unknown. Initially AQP1 was coined CHIP28 for CHannel forming Integral membrane Protein of 28 kDa. It was'nt until 1991, Peter Agres research group discovered the functional characteristics of AQP1. In 1993, CHIP23 was renamed AQP1. Since then, 12 other isoforms of aquaporin-1 have been discovered and each have been classified under the family known as Aquaporins.[2] Aquaporins are integral membrane proteins that specialize in the regulation of cellular water flow across the cell membrane.[3] This process is vital for any living organism to sustain proper physiological conditions and aquaporins are necessary to sustain this process (i.e. osmosis alone could not provide a sufficient flow of water). Extensive research on the function of aquaporins have been implemented into many separate types of cell membranes. Such membranes are from brain cells, kidney cells, muscle cells, red blood cells, and heart cells. Water selective aquaporins are AQP1, -2, -4, -5, -6, -8, -12, and -0. A subgroup of aquaporins called aquaglycerporins allow the passage of small solutes such as glycerol, urea, and ammonia. Aquaglyceroporins are AQP3, -7, -9, and -10.[2] Aquaporin-1 StructureAquaporin-1 is an integral membrane protein that is considered to have an "open" structure. Despite being "open", AQP1 has a high selectivity for the bidirectional transport of water, that even excludes small molecules such as hydrogen ions. AQP1 is formed as a tetramer in vivo, with each AQP1 monomer unit capable of transportation at a rate of ~2 trillion water molecules per second.[4]  An AQP1 monomer unit contains six highly tilted transmembrane α-helices and two internal α-helices, oriented in the form of a barrel. The transmembrane α-helices thread through the membrane so as to expose both the N- and the C-terminus to the inner cytoplasm. The aqueous pathway within the monomer unit is characterized by a narrow curvilinear pore that is ~4.0Å in diameter, ~18Å in length, and bends ~25 degrees as it transverses the membrane.[4] The curvilinear pore is a size selective pathway for water that excludes other larger and smaller molecules. The entrances to the aqueous pathway are mostly lined with polar and charged residues. Conversely, the interior of the aqueous pathway is mostly constituted by nonpolar residues. This feature allows for a relatively noninteracting pathway for the diffusion of water. To visualize the channel, we can place pseudoatoms into it (using the PACUPP scripts). There is a bottleneck in the channel that acts as a filter. Cations like potassium or sodium ions, even though they are smaller than water, do not pass because together with a layer of hydration, they are larger than water. The N- and C-terminal halves of AQP1 are tandem repeats that contain a conserved Asn-Pro-Ala (NPA) tripeptide sequence.[4] Each terminal half is composed of three tilted transmembrane α-helices and a short α-helix adjacent to the conserved NPA motif. The two halves are connected through transmembrane 3 (TM3) and TM4 by a long interhelix chain. The location of the two NPA tripeptide sequences define the apex of the curvilinear pathway (N76 & N192), which is located about the center of the membrane. This orientation of helices allows for a sufficient amount of noncovalent interactions to induce stability. Interactions between helices are dominantly hydrophobic. However, hydrogen-bond interactions have also been suggested to increase stability. AQP1 takes the form of a tetramer in vivo. The Quaternary interactions between monomeric units are both hydrophobic and polar. Within the membrane, monomer interactions are dominantly hydrophobic. Whereas hydrogen-bonding dominates nocovalent interactions outside the membrane. The transmembrane α-helices of each monomer are oriented so TM1, TM2, TM4, and TM5 define the interior of the AQP1 monomer (i.e. these helices face the other monomer units). TM3 and TM6 are defined as the membrane exposed exterior face.[4] Aquaporin-1 RegulationAquaporin channels may be subject to intense short term regulation via signal transduction. Transducers act as extracellular signal molecules that induce a response from membrane proteins. Protein Kinase C (PKC) has been documented as a common signal transducer among the aquaporins. One study suggests the positive relationship between PKC and AQP1.[5] In the presence of PKC, AQP1 was reported to have increased aqueous permeability. Phosphorylation of the amino acid Thr157 on the AQP1 protein by PKC is attributed to the increased permeability. The increased activity of AQP1 in the presence of PKC may contribute to the stimulation of physiological processes that are modulated by AQP1 such as endothelial permeability, angiogenesis, and urea concentration.
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