Editing Cytochrome c oxidase (section)

== Assembly ==

COX assembly in [[S. cerevisiae|yeast]] are a complex process that is not entirely understood due to the rapid and irreversible aggregation of hydrophobic subunits that form the holoenzyme complex, as well as aggregation of mutant subunits with exposed hydrophobic patches.<ref name = "pmid16760263"/> COX subunits are encoded in both the nuclear and mitochondrial genomes. The three subunits that form the COX catalytic core are encoded in the mitochondrial genome. Over 30 different nuclear-encoded chaperone proteins are required for COX assembly.<ref>{{Cite journal |last1=Dickinson |first1=Elizabeth K. |last2=Adams |first2=Denise L. |last3=Schon |first3=Eric A. |last4=Glerum |first4=D. Moira |date=September 2000 |title=A Human SCO2 Mutation Helps Define the Role of Sco1p in the Cytochrome Oxidase Assembly Pathway |journal=Journal of Biological Chemistry |language=en |volume=275 |issue=35 |pages=26780–26785 |doi=10.1016/S0021-9258(19)61443-2|doi-access=free |pmid=10854440 }}</ref>

Cofactors, including hemes, are inserted into subunits I & II. The two heme molecules reside in subunit I, helping with transport to subunit II where two copper molecules aid with the continued transfer of electrons.<ref>{{cite web | first = Antony | last = Crofts | name-list-style = vanc | date = 1996 | title = Cytochrome oxidase: Complex IV | publisher = University of Illinois at Urbana-Champaign | url = http://www.life.illinois.edu/crofts/bioph354/cyt_ox.html | access-date = 2018-01-28 | archive-date = 2018-01-23 | archive-url = https://web.archive.org/web/20180123023311/http://www.life.illinois.edu/crofts/bioph354/cyt_ox.html | url-status = live }}</ref> Subunits I and IV initiate assembly. Different subunits may associate to form sub-complex intermediates that later bind to other subunits to form the COX complex.<ref name = "pmid16760263"/> In post-assembly modifications, COX will form a homodimer. This is required for activity. Dimers are connected by a [[cardiolipin]] molecule,<ref name="pmid16760263">{{cite journal | vauthors = Fontanesi F, Soto IC, Horn D, Barrientos A | title = Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process | journal = American Journal of Physiology. Cell Physiology | volume = 291 | issue = 6 | pages = C1129-47 | date = December 2006 | pmid = 16760263 | doi = 10.1152/ajpcell.00233.2006 }}</ref><ref name="pmid16199211">{{cite journal | vauthors = Khalimonchuk O, Rödel G | title = Biogenesis of cytochrome c oxidase | journal = Mitochondrion | volume = 5 | issue = 6 | pages = 363–88 | date = December 2005 | pmid = 16199211 | doi = 10.1016/j.mito.2005.08.002 }}</ref><ref name = "pmid26284624">{{cite journal | vauthors = Sedlák E, Robinson NC | title = Destabilization of the Quaternary Structure of Bovine Heart Cytochrome c Oxidase upon Removal of Tightly Bound Cardiolipin | journal = Biochemistry | volume = 54 | issue = 36 | pages = 5569–77 | date = September 2015 | pmid = 26284624 | doi = 10.1021/acs.biochem.5b00540 }}</ref> which has been found to play a key role in stabilization of the holoenzyme complex. The dissociation of subunits VIIa and III in conjunction with the removal of cardiolipin results in total loss of enzyme activity.<ref name = "pmid26284624"/> Subunits encoded in the nuclear genome are known to play a role in enzyme dimerization and stability. Mutations to these subunits eliminate COX function.<ref name = "pmid16760263"/>

Assembly is known to occur in at least three distinct rate-determining steps. The products of these steps have been found, though specific subunit compositions have not been determined.<ref name = "pmid16760263"/>

Synthesis and assembly of COX subunits I, II, and III are facilitated by translational activators, which interact with the 5’ untranslated regions of mitochondrial mRNA transcripts. Translational activators are encoded in the nucleus. They can operate through either direct or indirect interaction with other components of translation machinery, but exact molecular mechanisms are unclear due to difficulties associated with synthesizing translation machinery in-vitro.<ref name = "pmid22450032">{{cite journal | vauthors = Herrmann JM, Woellhaf MW, Bonnefoy N | title = Control of protein synthesis in yeast mitochondria: the concept of translational activators | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1833 | issue = 2 | pages = 286–94 | date = February 2013 | pmid = 22450032 | doi = 10.1016/j.bbamcr.2012.03.007 | doi-access = free }}</ref><ref name = "pmid21958598">{{cite journal | vauthors = Soto IC, Fontanesi F, Liu J, Barrientos A | title = Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1817 | issue = 6 | pages = 883–97 | date = June 2012 | pmid = 21958598 | pmc = 3262112 | doi = 10.1016/j.bbabio.2011.09.005 }}</ref> Though the interactions between subunits I, II, and III encoded within the mitochondrial genome make a lesser contribution to enzyme stability than interactions between bigenomic subunits, these subunits are more conserved, indicating potential unexplored roles for enzyme activity.<ref name = "pmid4255772">{{cite journal | vauthors = Aledo JC, Valverde H, Ruíz-Camacho M, Morilla I, López FD | title = Protein-protein interfaces from cytochrome c oxidase I evolve faster than nonbinding surfaces, yet negative selection is the driving force | journal = Genome Biology and Evolution | volume = 6 | issue = 11 | pages = 3064–76 | date = October 2014 | pmid = 25359921 | pmc = 4255772 | doi = 10.1093/gbe/evu240 }}</ref>