Structural and Physiological Factors Controlling the Ion Specificity of ATP Synthase Membrane Rotors

Abstract

ATP synthases are large multi-subunit complexes that utilize the energy stored in transmembrane electrochemical gradients of H(+) or Na(+) for the synthesis of ATP, through a rotary mechanism. A membrane-embedded sub-complex, known as the rotor ring, is the key structural component that transforms the free-energy gained from downhill ion transport into mechanical rotation. The rotor ring thus confers the ATP synthase with its ion specificity, influencing the degree to which cell-growth will be viable in a given physiological context. Here, we review our understanding of the principles that control the ion specificity of ATPase/synthase membrane rotors, based upon extensive theoretical work and biochemical and structural data for a range of representative organisms. In particular, we discuss how a conserved E/D side chain provides the ion-binding sites of all rotors across the F, V and A-ATPase/synthase subfamilies with a strong, intrinsic selectivity for protons. This default specificity, however, is somehow drastically enhanced or reduced to allow for actual H(+) or Na(+) coupling under physiological conditions. We show that such strong modulation is provided by the spectrum of non-conserved amino-acids that decorate the ion-binding sites. While hydrophobic side chains contribute to enhance the H(+) selectivity of the rotors to the extreme levels required in many cases, polar side-chains and structurally-bound water molecules have the opposite effect, and can make a binding site essentially non-specific - which facilitates Na(+)-coupling. Altogether, this analysis illustrates a process of adaptation in the chemical structure of an indispensable enzyme, so as to meet the requirements of a given physiological environment.