Affinage

CMC2

COX assembly mitochondrial protein 2 homolog · UniProt Q9NRP2

Round 2 corrected
Length
79 aa
Mass
9.5 kDa
Annotated
2026-04-28
35 papers in source corpus 1 papers cited in narrative 4 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CMC2 is a mitochondrial inner membrane protein with a twin Cx9C motif that faces the intermembrane space and is essential for cytochrome c oxidase (COX) assembly and cellular respiration; loss of CMC2 abolishes COX activity and oxygen consumption (PMID:20220131). CMC2 physically interacts with its paralog CMC1 and regulates CMC1 stability, yet the two proteins perform non-overlapping cooperative functions in COX biogenesis (PMID:20220131). CMC2 also modulates mitochondrial copper delivery to CuZn-superoxide dismutase (Sod1), linking it to mitochondrial copper metabolism, and its role in COX assembly is functionally conserved from yeast to C. elegans and humans (PMID:20220131).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2010 High

    Establishing CMC2 as essential for COX biogenesis resolved what the twin Cx9C protein Cmc2 does: it is required in the mitochondrial inner membrane/IMS for cytochrome c oxidase activity and aerobic respiration.

    Evidence Yeast cmc2Δ mutant analyzed by spectrophotometric COX activity assay and polarographic respiration measurement, with subcellular fractionation confirming IMS-facing inner membrane localization

    PMID:20220131

    Open questions at the time
    • No direct substrate or client protein within the COX assembly pathway has been identified for CMC2
    • Structural basis of CMC2 function and its twin Cx9C motif redox state remain uncharacterized
    • Whether CMC2 acts catalytically or as a structural scaffold in COX assembly is unknown
  2. 2010 High

    Demonstrating that CMC2 physically interacts with its paralog CMC1 and controls CMC1 turnover—yet cannot be rescued by CMC1 overexpression—established that the two proteins cooperate through distinct, non-redundant mechanisms in COX biogenesis.

    Evidence Co-immunoprecipitation, Western blotting of mitochondrial fractions showing 5-fold CMC1 accumulation in cmc2Δ, and reciprocal genetic non-complementation in yeast

    PMID:20220131

    Open questions at the time
    • The stoichiometry and topology of the CMC1–CMC2 complex are unresolved
    • How CMC2 promotes CMC1 turnover (protease involvement, oxidative folding) is unknown
  3. 2010 Medium

    Linking CMC2 to mitochondrial Sod1 activity placed CMC2 in the copper delivery pathway, suggesting it influences copper distribution between COX and Sod1 in the intermembrane space.

    Evidence Sod1 enzymatic activity assays in cmc2Δ and CMC2-overexpressing yeast strains

    PMID:20220131

    Open questions at the time
    • Single-lab observation not independently confirmed
    • Whether CMC2 binds copper directly has not been tested
    • Mechanism by which CMC2 partitions copper between COX and Sod1 is uncharacterized
  4. 2010 High

    Showing that human CMC2 localizes to mitochondria and that C. elegans CMC2 knockdown phenocopies COX deficiency established functional conservation across eukaryotes.

    Evidence Subcellular localization of human CMC2 to mitochondria; RNAi knockdown with COX activity assay in C. elegans

    PMID:20220131

    Open questions at the time
    • Human CMC2 loss-of-function in mammalian cells has not been biochemically characterized
    • No disease-associated mutations in CMC2 have been reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include whether CMC2 directly binds copper, what its specific client(s) within the COX assembly pathway are, and whether CMC2 mutations cause mitochondrial disease in humans.
  • No in vitro copper-binding or metallochaperone reconstitution data exist
  • No structural information for CMC2 or the CMC1–CMC2 complex
  • Mammalian genetic models (knockout mice, patient mutations) have not been reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005739 mitochondrion 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
CMC1

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Yeast Cmc2 localizes to the mitochondrial inner membrane facing the intermembrane space, as established by subcellular fractionation, and is essential for cytochrome c oxidase (COX) activity and cellular respiration; in the absence of Cmc2, COX activity measured spectrophotometrically and cellular respiration measured polarographically are undetectable. Subcellular fractionation, spectrophotometric enzyme activity assay, polarographic respiration measurement, yeast deletion mutant The Journal of biological chemistry High 20220131
2010 Cmc2 physically interacts with Cmc1 (a paralogous twin Cx9C intermembrane space protein), as shown by co-immunoprecipitation; loss of Cmc2 causes a 5-fold increase in Cmc1 accumulation in mitochondrial membranes, indicating that Cmc2 modulates Cmc1 stability/turnover. Overexpression of CMC1 cannot rescue the respiratory defect of cmc2 mutants and vice versa, demonstrating non-overlapping cooperative functions. Co-immunoprecipitation, Western blotting of mitochondrial membrane fractions, genetic complementation analysis The Journal of biological chemistry High 20220131
2010 Cmc2 affects mitochondrial CuZn-superoxide dismutase (Sod1) activity: cmc2 deletion cells display 2-fold increased mitochondrial Sod1 activity, whereas CMC2 overexpression reduces Sod1 activity to ~60% of wild-type, implicating Cmc2 in mitochondrial copper metabolism and delivery. Enzymatic activity assay (Sod1 activity measurement), yeast deletion and overexpression strains The Journal of biological chemistry Medium 20220131
2010 CMC2 function is conserved in humans: human CMC2 localizes to mitochondria (confirmed by direct localization experiment), and siRNA knockdown of CMC2 in Caenorhabditis elegans produces cytochrome c oxidase deficiency, demonstrating functional conservation from yeast to metazoans. Mitochondrial localization by subcellular fractionation/imaging, RNAi knockdown in C. elegans with COX activity assay The Journal of biological chemistry High 20220131

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2016 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. Molecular cell 220 27499296
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2008 Systematic identification of mRNAs recruited to argonaute 2 by specific microRNAs and corresponding changes in transcript abundance. PloS one 148 18461144
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2021 SARS-CoV-2-host proteome interactions for antiviral drug discovery. Molecular systems biology 86 34709727
2017 The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nature communications 86 29180619
2013 DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells. PLoS pathogens 61 23825944
2011 Potential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility. Human genetics 39 21424380
2018 Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II. Nature communications 37 30349055
2011 Proteomic dissection of the von Hippel-Lindau (VHL) interactome. Journal of proteome research 36 21942715
2010 The conserved mitochondrial twin Cx9C protein Cmc2 Is a Cmc1 homologue essential for cytochrome c oxidase biogenesis. The Journal of biological chemistry 34 20220131
2013 Prostate cancer stem cell-targeted efficacy of a new-generation taxoid, SBT-1214 and novel polyenolic zinc-binding curcuminoid, CMC2.24. PloS one 33 24086245
2020 Chemically modified curcumin (CMC2.24) alleviates osteoarthritis progression by restoring cartilage homeostasis and inhibiting chondrocyte apoptosis via the NF-κB/HIF-2α axis. Journal of molecular medicine (Berlin, Germany) 29 32860098
2016 TNIP2 is a Hub Protein in the NF-κB Network with Both Protein and RNA Mediated Interactions. Molecular & cellular proteomics : MCP 28 27609421
2021 Acetylation of ELF5 suppresses breast cancer progression by promoting its degradation and targeting CCND1. NPJ precision oncology 22 33742100
2018 Infected erythrocytes expressing DC13 PfEMP1 differ from recombinant proteins in EPCR-binding function. Proceedings of the National Academy of Sciences of the United States of America 22 29339517
2020 In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators. PLoS biology 16 33306668
2009 Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects. European journal of human genetics : EJHG 14 19844255
2018 A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras. Molecular carcinogenesis 12 29683208
2021 Elucidation of the BMI1 interactome identifies novel regulatory roles in glioblastoma. NAR cancer 11 34316702
2022 TRABID targets DDB2 for deubiquitination to promote proliferation of hepatocellular carcinoma cells. Biochemical and biophysical research communications 9 35944360
2021 IgG acquisition against PfEMP1 PF11_0521 domain cassette DC13, DBLβ3_D4 domain, and peptides located within these constructs in children with cerebral malaria. Scientific reports 9 33574457
2003 The dc13 gene upstream of ictB is involved in rapid induction of the high affinity Na(+) dependent HCO(3) (-) transporter in cyanobacteria. Photosynthesis research 8 16228371
2002 Cloning and transcription analysis of the Aspergillus aculeatus No. F-50 endoglucanase 2 (cmc2) gene. Journal of bioscience and bioengineering 6 16233338
2023 Efficacy of a Novel Pleiotropic MMP-Inhibitor, CMC2.24, in a Long-Term Diabetes Rat Model with Severe Hyperglycemia-Induced Oral Bone Loss. Journal of inflammation research 5 36860795
2023 Novel Hydrogenated Derivatives of Chemically Modified Curcumin CMC2.24 Are Potent Inhibitors of Melanogenesis in an In Vitro Model: Influence of Degree of Hydrogenation. Life (Basel, Switzerland) 2 37374155
1988 [Study of Pseudomonas aeruginosa DC13 stability during biological purification of industrial sewage from alpha-methyl styrene]. Mikrobiologiia 1 3150519
2026 Transcriptomics and proteomics insights into carotenoid differentiation in tissue cultured Rehmannia glutinosa root cambial meristematic cells: REG-CMC1 and non-somaclonal REG-CMC2. BMC plant biology 0 41688906