The Aquaporin (AQP) Family
The cells of all life forms are surrounded by a membrane and filled with water. Although simple lipid bilayers exhibit limited water permeability, membranes of red cells, cells in renal proximal tubules and in certain other tissues are extremely permeable to water. Water-selective membrane channel proteins were predicted in these tissues to explain the high water permeability (low activation energy) and reversible inhibition by mercuric ions. Aquaporin-1 (AQP1), initially found in human red blood cells, was the first identified water pore. The discovery of AQP1 has led to the identification of many more (>300) family members in bacteria, fungi, plants, insects, and higher animals, including humans. Since members of the AQP family are found in almost every organism, the number of proteins belonging to this family increases rapidly as the sequences of new genomes become available. The phylogenetic tree shows two major clusters of aquaporins, the AQPs (pure water channels) and GLPs (channels for water and small non-ionic solutes). The two major families emerged billions of years ago from an ancient bacterial channel protein.
AQPs have to be highly specific for water to prevent other solutes and ions from also crossing the membrane. Protons present a particularly difficult challenge, because the positive charge of a proton can move along a column of water by hydrogen bond exchange. Since proton fluxes across cellular membranes drive physiological processes, such as membrane fusion, vesicular transport, solute transport and ATP synthesis, proton leakage across the membrane must be avoided. Work on AQPs has significantly influenced investigations of the biophysics of water permeation across cell membranes, the physiology of fluid transport in the kidney and other organs, and the pathophysiological basis of inherited and acquired disorders of water balance. For his discovery of water channels, Peter Agre (Johns Hopkins University School of Medicine) received the 2003 Nobel Prize in Chemistry.
See Aquaporin-0 in the Cell Adhesion section.
Aquaporin-1 (AQP1), discovered
in 1988, is the third most abundant protein in red blood cell
membranes. It functions as a very specific
water conducting pore, and it is also expressed in segments of
the kidney that are known to exhibit very high water permeability.
first insight into the structure and function of AQP1 came from
sequence analyses and expression studies in Xenopus
monomer contains 269 amino acid residues, which form two tandem
repeats of three membrane-spanning α-helices with amino- and
carboxy-termini located on the cytoplasmic side of the membrane. In
the hourglass model, connecting loops B (cytoplasmic) and E (extracellular)
each contain the consensus motif Asn-Pro-Ala (NPA) and dip into the
from the opposite sides where they overlap, forming a single transmembrane
aqueous pathway through each subunit of the AQP1 tetramer. Reconstitution
of highly purified human red cell AQP1 into well-ordered membrane
crystals has permitted definition of AQP1 structure at increasingly
higher levels of resolution. Finally, it was possible to build
a model for AQP1 into a 3.8 Å density map, generating the first
atomic structure for a member of the AQP family. Multiple highly conserved
amino acid residues stabilize the novel fold of AQP1. The aqueous
pathway is lined with conserved hydrophobic residues that permit
rapid water permeation, whereas the water selectivity is due to a
constriction of the pore diameter to about 3 Å over a span of
one residue. The atomic model provided a possible molecular explanation
to a longstanding puzzle in physiology – how membranes can be
freely permeable to water but impermeable to protons.