Download MendeleyRole of conformational change and K-path ligands in controlling cytochrome c oxidase activity.
Liu, J., Hiser, C., Ferguson-Miller, S.(2017) Biochem Soc Trans 45: 1087-1095
- PubMed: 28842531
- DOI: https://doi.org/10.1042/BST20160138
- Primary Citation of Related Structures:
5WEH - PubMed Abstract:
Given the central role of cytochrome c oxidase (C c O) in health and disease, it is an increasingly important question as to how the activity and efficiency of this key enzyme are regulated to respond to a variety of metabolic states. The present paper summarizes evidence for two modes of regulation of activity: first, by redox-induced conformational changes involving the K-proton uptake path; and secondly, by ligand binding to a conserved site immediately adjacent to the entrance of the K-path that leads to the active site. Both these phenomena highlight the importance of the K-path in control of C c O. The redox-induced structural changes are seen in both the two-subunit and a new four-subunit crystal structure of bacterial C c O and suggest a gating mechanism to control access of protons to the active site. A conserved ligand-binding site, first discovered as a bile salt/steroid site in bacterial and mammalian oxidases, is observed to bind an array of ligands, including nucleotides, detergents, and other amphipathic molecules. Highly variable effects on activity, seen for these ligands and mutations at the K-path entrance, can be explained by differing abilities to inhibit or stimulate K-path proton uptake by preventing or allowing water organization. A new mutant form in which the K-path is blocked by substituting the conserved carboxyl with a tryptophan clarifies the singularity of the K-path entrance site. Further study in eukaryotic systems will determine the physiological significance and pharmacological potential of ligand binding and conformational change in C c O.
Organizational Affiliation:
Department of Biochemistry and Molecular Biology, Michigan State University, 603 Wilson Rd, East Lansing, MI 48824, U.S.A.
