Abstract
Aquaporins (AQPs) are among the best structural-characterized membrane proteins, fulfilling the role of allowing water flux across cellular membranes. Thus far, 34 single amino acid polymorphisms have been reported in HUMSAVAR for human aquaporins as disease-related. They affect AQP2, AQP5 and AQP8, where they are associated with nephrogenic diabetes insipidus, keratoderma and colorectal cancer, respectively. For half of these mutations, although they are mostly experimentally characterized in their dysfunctional phenotypes, a structural characterization at a molecular level is still missing. In this work, we focus on such mutations and discuss what the structural defects are that they appear to cause. To achieve this aim, we built a 3D molecular model for each mutant and explored the effect of the mutation on all of their structural features. Based on these analyses, we could collect the structural defects of all the pathogenic mutations (here or previously analysed) under few main categories, that we found to nicely correlate with the experimental phenotypes reported for several of the analysed mutants. Some of the structural analyses we present here provide a rationale for previously experimentally observed phenotypes. Furthermore, our comprehensive overview can be used as a reference frame for the interpretation, on a structural basis, of defective phenotypes of other aquaporin pathogenic mutants.
Highlights
Aquaporins (AQPs) are highly selective transmembrane channel proteins, which allow flux of water and small solutes across biological membranes in a large variety of organisms [1]
Human AQP11 and AQP12 are hardly classifiable as either classical aquaporins or aquaglyceroporins. They have been proposed as a third group, the superaquaporins [10] or subcellular aquaporins, according to their cellular localisation [11], they seem to preserve the structural arrangement of other aquaporins [12]
In OMIM [68] overall 20 single amino acid polymorphisms (SAPs) are reported for AQPs (15 for AQP12 and 5 for AQP5), representing a subset of the 34 SAPs reported in HUMSAVAR
Summary
Aquaporins (AQPs) are highly selective transmembrane channel proteins, which allow flux of water and small solutes across biological membranes in a large variety of organisms [1]. Orthodox aquaporins are selective for water, while aquaglyceroporins are permeable to glycerol and other small, polar solutes [1]. Four human AQPs, AQP3, AQP7, AQP9 and AQP10, are instead classified as aquaglyceroporins, being permeable to glycerol and other small solutes such as urea and/or ammonia [9]. Human AQP11 and AQP12 are hardly classifiable as either classical aquaporins or aquaglyceroporins. They have been proposed as a third group, the superaquaporins [10] or subcellular aquaporins, according to their cellular localisation [11], they seem to preserve the structural arrangement of other aquaporins [12]
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