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p.2 left column 2nd paragraph:"Although under-represented in the human proteome with ~2% frequency (Webb et al., 2011), histidines are found in critical regions of G-protein coupled receptors, GPCRs (OGR1 and GPR4), intracellular molecules involved in actin assembly (Talin and Cofilin), membrane proton pumps and acid-sensing ion channels, ASICs (Schonichen et al., 2013b). Protonation and de-protonation has been experimentally shown to change protein structure and thus, alter protein-protein binding affinity, change protein stability, modify protein function, and alter subcellular localization (Schonichen et al., 2013b). Evolutionarily, histidines must confer some selective advantage for cancers, as 15% of the 2000 identified somatic mutations in cancer involve histidine subsitutions, with Arg-to-His being the most frequent (primary source)." |