Regulation by pH Sensors and Signaling Modes

One advantage of using protons for signaling and regulation as opposed to posttranslational modifications or cofactors is the potential for extremely rapid temporal responses. Protons can diffuse through water exceptionally quickly (“Grotthuss diffusion,” made possible in part by the quantum mechanical tunneling ability of protons), possibly facilitated by short-range motion in proteins (58). The variation of pH among subcellular locales makes possible spatial regulation as well. Protons also present an elegant means of regulating protein activity and interactions. A proton is an exceptionally small single subatomic particle that can induce a reversible chemical change resulting in substantial electrostatic perturbation, which can drive changes in protein structure, dynamics, and interactions. As a regulator of protein function, protons can be used in multiple signaling modes. The Bohr effect of pH-driven changes in the affinity of hemoglobin for oxygen binding is the classic example of a single-site, proton-induced allosteric regulation. The effect of pH is mediated by a His-Asp salt bridge (His146 and Asp94 in human hemoglobin), which is disrupted when His146 is deprotonated at increased pH. However, electrostatic interactions, particularly due to chloride binding, also affect proton exchange at His146 (reviewed in Ref. 53). Cooperativity involving binding of ligands or electrostatic coupling of multiple proton binding sites play pivotal roles in pH sensing (28, 95, 115). An example of thermodynamic linkage is the HIV-1 protease, which is required for the formation of mature virions.