A CLUSTER OF CYTOPLASMIC HISTIDINE-RESIDUES SPECIFIES PH-DEPENDENCE OF THE AE2 PLASMA-MEMBRANE ANION-EXCHANGER

Intracellular pH is maintained by a dynamic equilibrium balancing the opposing forces of proton loading and proton extrusion. By providing a n efflux pathway for base, anion exchangers constitute a key component of the plasma membrane proton-loading machinery. The data in this pap er identify a histidine-rich sequence within the cytoplasmic domain of the nonerythroid anion exchanger, AE2, that serves as an intracellula r pH ''sensor'' that modulates anion exchange activity within the phys iological range of cytoplasmic pH. These data reveal an interaction be tween the two major domains of the anion exchanger and suggest a novel substrate feedback mechanism by which intracellular protons directly control the activity of an acid-loading plasma membrane ion transporte r.