The biogenesis and assembly of the human ATP synthase

The human ATP synthase is an assembly of 29 proteins of 18 different kinds (including the regulatory protein IF1). The ATP6 and ATP8 subunits (subunits a and A6L, respectively) are encoded by overlapping genes in mitochondrial DNA [1], and the remainder are the products of nuclear genes that are imported into the organelle.

Figure Isoforms of subunit c. The red bars show the positions of the transmembrane helices.

The c-subunit, which forms a c8-ring in the membrane bound part of the rotor, is encoded by three human genes ATP5G1, ATP5G2 and ATP5G3 [2] [3]. The gene products differ in the import sequences at the N-terminus of the mitochondrial import precursor. Removal of these three N-terminal sequences during the process of import into mitochondria generates an identical mature c-subunit. The other subunits are encoded by single genes.

Figure Isoforms of subunit fThe red bar shows the predicted transmembrane helix.

Two forms of subunit f are generated by alternate splicing, and both forms are found in human cells. Lysine residue-43 in the c-subunit is completely trimethylated [4], and both the c8-ring and the complete trimethylation of lysine-43 persist throughout metazoans, but not elsewhere [5].


The aims are as follows:


  • to define the pathway(s) of assembly of the complex, and to identify any exogenous proteins involved in the process of assembly
  • to identify the protein methylase that modifies the c-subunit, and to investigate the role of methylation of this subunit in the assembly pathway of ATP synthase