Biochemistry, Department of


Date of this Version



The Journal of Biological Chemistry, VOL. 287, NO. 32, pp. 26715–26726, August 3, 2012


© 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


The synthesis of the heme a cofactor used in cytochrome c

oxidase (CcO) is dependent on the sequential action of heme o

synthase (Cox10) and heme a synthase (Cox15). The active state of

Cox10 appears to be a homo-oligomeric complex,andformation of

this complex is dependent on the newly synthesized CcO subunit

Cox1 and the presence of an early Cox1 assembly intermediate.

Cox10 multimerization is triggered by progression of Cox1 from

the early assembly intermediate todownstreamintermediates.The

CcOassembly factor Coa2 appears important in coupling the presence

of newly synthesized Cox1 to Cox10 oligomerization. Cells

lacking Coa2 are impaired in Cox10 complex formation as well as

the formation of a high mass Cox15 complex. Increasing Cox1 synthesis

in coa2∆cells restores respiratory function if Cox10 protein

levels are elevated.TheC-terminalsegmentofCox1is important in

triggering Cox10 oligomerization. Expression of the C-terminal 54

residues of Cox1 appended to a heterologous matrix protein leads

to efficient Cox10 complex formation in coa2∆ cells, but it fails to

induce Cox15 complex formation. The state of Cox10 was evaluated

in mutants, which predispose human patients to CcO deficiency

and the neurological disorder Leigh syndrome. The presence

of theD336Vmutation in the yeast Cox10 backbone results in

a catalytically inactive enzyme that is fully competent to oligomerize.

Thus, Cox10 oligomerization and catalytic activation are separate

processes and can be uncoupled.