Structure and function of aquaporin water channels

The aquaporins (AQPs) are a family of small membrane-spanning proteins (mon omer size similar to 30 kDa) that are expressed at plasma membranes in many cells types involved in fluid transport. This review is focused on the mol ecular structure and function of mammalian aquaporins. Basic features of aq uaporin structure have been defined using mutagenesis, epitope tagging, and spectroscopic and freeze-fracture electron microscopy methods. Aquaporins appear to assemble in membranes as homotetramers in which each monomer, con sisting of six membrane-spanning alpha-helical domains with cytoplasmically oriented amino and carboxy termini, contains a distinct water pore. Medium -resolution structural analysis by electron cryocrystallography indicated t hat the six tilted helical segments form a barrel surrounding a central por e-like region that contains additional protein density. Several of the mamm alian aquaporins (e.g., AQP1, AQP2, AQP4, and AQP5) appear to be highly sel ective for the passage of water, whereas others (recently termed aquaglycer oporins) also transport glycerol (e.g.,AQP3 and AQP8) and even larger solut es (AQP9). Evidence for possible movement of ions and carbon dioxide throug h the aquaporins is reviewed here, as well as evidence for direct regulatio n of aquaporin function by posttranslational modification such as phosphory lation. Important unresolved issues include definition of the molecular pat hway through which water and solutes move, the nature of monomer-monomer in teractions, and the physiological significance of aquaporin-mediated solute movement. Recent results from knockout mice implicating multiple physiolog ical roles of aquaporins suggest that the aquaporins may be suitable target s for drug discovery by structure-based and/or high-throughput screening st rategies.