Functional effects of mutations in cytochrome c oxidase related to prostate cancer
2011 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1807, no 10, 1336-1341 p.Article in journal (Refereed) Published
A number of missense mutations in subunit I of cytochrome c oxidase (CytcO) have previously been linked to prostate cancer (Petros et al. (2005) PNAS, 102, 719). To investigate the effects of these mutations at the molecular level, in the present study we prepared four different structural variants of the bacterial Rhodobacter sphaeroides CytcO (cytochrome aa3), each carrying one amino-acid residue replacement corresponding to the following substitutions identified in the above-mentioned study: Asn11Ser, Ala122Thr, Ala341Ser and Val380Ile (residues Asn25, Ser168, Ala384 and Val423 in the R. sphaeroides oxidase). This bacterial CytcO displays essentially the same structural and functional characteristics as those of the mitochondrial counterpart. We investigated the overall activity, proton pumping and internal electron- and proton- transfer reactions in the structural variants. The results show that the turnover activities of the mutant CytcOs were reduced by at most a factor of two. All variants pumped protons, but in Ser168Thr, Ala384Ser and Val423Ile we observed slight internal proton leaks. In all structural variants the internal electron equilibrium was slightly shifted away from the catalytic site at high pH (10), resulting in a slower observed ferryl to oxidized transition. Even though the effects of the mutations were relatively modest, the results suggest that they destabilize the proton-gating machinery. Such effects could be manifested in the presence of a transmembrane electrochemical gradient resulting in less efficient energy conservation.
Place, publisher, year, edition, pages
2011. Vol. 1807, no 10, 1336-1341 p.
Respiration, Proton pumping, Electron transfer, Cytochrome aa3, Mitochondria, Membrane protein
Research subject Biochemistry
IdentifiersURN: urn:nbn:se:su:diva-65338DOI: 10.1016/j.bbabio.2011.02.005ISI: 000294513600011OAI: oai:DiVA.org:su-65338DiVA: diva2:465860