Cytochrome C Oxidase Subunit III

Cytochrome C oxidase is an integral membrane complex of up to 13 components in bacteria and mitochondria of which subunit III (designated chain C in 2occ, Figure 10.3A) is a 7TM "receptor" of unknown function. The helices of subunit III can be over 30 residues long, have no features in common with GPCRs, and form a topography similar to a Greek-key spiral when viewed from the amino terminal face. The void between TM2 and TM3 is partially filled by phosphatidylcholine aligned along TM3 in the bacterial structure. The quaternary ammonium and phosphate

FIGURE 10.3 Broad diversity of known receptor 3D structures and topologies. A, a Ca ribbon trace of bovine mitochondrial cytochrome c oxidase (PDB code, 2occ) looking from the matrix space and from within the inner mitochondrial membrane to reveal the association of two 7TM subunit III molecules and their peptide 'ligands' provided by subunits V-B and VII-A. Comparative topologies of bovine rhodopsin (1hzx), subunit III (2occ) and human aquaporin (1fx8) from within the plane of the membrane, B, and diagrammatically from above, C. TM3 is produced from two independent half-helices in aquaporin.

FIGURE 10.3 Broad diversity of known receptor 3D structures and topologies. A, a Ca ribbon trace of bovine mitochondrial cytochrome c oxidase (PDB code, 2occ) looking from the matrix space and from within the inner mitochondrial membrane to reveal the association of two 7TM subunit III molecules and their peptide 'ligands' provided by subunits V-B and VII-A. Comparative topologies of bovine rhodopsin (1hzx), subunit III (2occ) and human aquaporin (1fx8) from within the plane of the membrane, B, and diagrammatically from above, C. TM3 is produced from two independent half-helices in aquaporin.

groups of the lipid head group are attached noncovalently via ion pairs to Glu74 and Arg233 of the closely apposed helices TM2 and TM6, respectively.12 The crystal structure of cytochrome C oxidase reveals the 13 component complexes have a dimer interface predominantly formed by apposition of two subunit III proteins. The amino terminal portion of subunit VII-A (chain J) forms a laterally oriented helix adjacent to the presumed membrane broaching of the helical bundle of subunit III, reminiscent of the disposition of helix 8 in the rhodopsin structure.

Intriguingly, the amino terminal portion of subunit V-B (chain F in 2occ) folds into two short helices that occupy the equivalent of the "ligand-binding surface" of a peptidic 7TMR. Only a few investigations have directly focused on the conformations of peptide ligands when bound to a 7TMR. As for most peptides up to ~40 residues long, little formal structure is evident in aqueous solution and the intrinsic amphiphilicity can only be assuaged by a hydrophobic folding focus. The conformations of PACAP(1-21)NH2 bound both to micelles and to the PACAP receptor (of the family B or secretin type) were studied using NMR.13 Residues 3-7 only produce a p-coil structure when bound to the receptor, whereas the 8-21 a-helix is evident in both bound conditions. The affinity of amphiphilic sequences for membranes offers the attractive prospect that flexible peptide ligands worm across cell surfaces in a search for their cognate serpentine receptors.

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