Practice question

Highly conserved sequence motif in aquaporin family defines aqueous pore architecture and selectivity. Loop B half-helix and Loop E half-helix each dip into membrane from opposite sides each containing invariant tripeptide Asn-Pro-Ala forming two NPA boxes meeting at center of channel creating electrostatic barrier and orienting water molecules in opposite NPA asparagine carbonyl hydrogen bond donors. Proline introduces kink allowing asparagine side chain to project into pore, alanine stabilizes packing between half-helix and transmembrane helices. Structural alignments show two NPA motifs generate constriction forcing water reorientation one hundred eighty degrees disrupting continuous hydrogen bonded chain required for proton hopping via Grotthuss mechanism, while arginine selectivity filter excludes ions. Mutation NPA to NPG or NPS in aquaporin-2 causes nephrogenic diabetes insipidus reducing water permeability and autosomal dominant cataract. Database search using NPA signature identifies over three hundred aquaporin orthologs across Bacteria E coli aquaporin Z, Archaea, plants tonoplast intrinsic proteins, mammals, distinguishing water channels from glycerol facilitators and ion channels lacking motif.