COX4I1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045277 respiratory chain complex IV	IBA GO_REF:0000033	ACCEPT	Summary: COX4I1 is a bona fide subunit of Complex IV (cytochrome c oxidase). Structural studies confirm it is one of 14 subunits of the intact monomeric CIV (PMID:30030519). This IBA annotation is well supported by phylogenetic inference across eukaryotes and by direct structural and biochemical evidence. Reason: Core component annotation. COX4I1 is one of the 14 subunits of Complex IV, confirmed by cryo-EM structure of the intact human CIV (PMID:30030519) and UniProt which lists it as "Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits." Phylogenetic inference (IBA) is entirely consistent. Supporting Evidence: PMID:30030519 we obtained the entire CIV structure containing 14 subunits, which includes the extra subunit NDUFA4 file:human/COX4I1/COX4I1-uniprot.txt Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and COXFA4
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	IBA GO_REF:0000033	ACCEPT	Summary: COX4I1, as a subunit of Complex IV, is involved in the process of electron transport from cytochrome c to oxygen. While COX4I1 does not directly participate in electron transfer (catalyzed by the mtDNA-encoded core subunits COX1/2/3), it is required for complex assembly, stability, and allosteric regulation of this process (PMID:30030519). IBA inference is well supported. Reason: Core biological process annotation. COX4I1 is essential for Complex IV function. Pathogenic variants in COX4I1 cause Complex IV deficiency (PMID:28766551), demonstrating it is required for electron transport from cytochrome c to oxygen. The IBA annotation is phylogenetically sound. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria...It accepts electrons from cytochrome c to reduce the oxygen to water and meanwhile pumps two protons from the matrix side to the intermembrane space (IMS) file:human/COX4I1/COX4I1-uniprot.txt Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1
GO:1902600 proton transmembrane transport	IEA GO_REF:0000108	ACCEPT	Summary: Complex IV couples electron transfer to proton pumping across the inner mitochondrial membrane. As a subunit of CIV, COX4I1 contributes to this process. The IEA annotation is derived from the logical inference that cytochrome-c oxidase activity (GO:0004129) implies proton transmembrane transport. Reason: Acceptable IEA inference. Complex IV pumps protons during electron transport, and COX4I1 as a structural/regulatory subunit is involved in this process. While COX4I1 does not directly form the proton channel, the annotation captures the broader process the complex participates in. Supporting Evidence: PMID:30030519 It accepts electrons from cytochrome c to reduce the oxygen to water and meanwhile pumps two protons from the matrix side to the intermembrane space (IMS)
GO:0005743 mitochondrial inner membrane	IEA GO_REF:0000120	ACCEPT	Summary: COX4I1 is a single-pass transmembrane protein of the mitochondrial inner membrane. This is confirmed by cryo-EM structural data (PMID:30030519) and UniProt annotation. Reason: Core localization confirmed by structural studies and multiple lines of evidence. COX4I1 has a transmembrane helix (residues 99-124) spanning the inner mitochondrial membrane, with a matrix-facing regulatory domain and an IMS-facing C-terminal segment. Supporting Evidence: file:human/COX4I1/COX4I1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane...Single-pass membrane protein PMID:30030519 we obtained the entire CIV structure containing 14 subunits
GO:0005758 mitochondrial intermembrane space	IEA GO_REF:0000117	ACCEPT	Summary: COX4I1 has a C-terminal segment (residues 125-169) that faces the intermembrane space, contacting COX2 to shape the cytochrome c docking site. However, COX4I1 is primarily an inner membrane protein with matrix and IMS domains, not a soluble IMS protein. This annotation is somewhat misleading as a localization statement. Reason: While COX4I1 is not a soluble IMS protein, it does have a topology domain in the intermembrane space (residues 125-169), making this annotation technically correct. UniProt topology annotation confirms this. The IEA prediction is consistent with the known topology. Supporting Evidence: file:human/COX4I1/COX4I1-uniprot.txt TOPO_DOM 125..169 /note="Mitochondrial intermembrane"
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate of the IBA annotation for the same GO term. This IEA annotation is based on InterPro domain mapping (IPR004203, IPR036639) to the COX subunit IV family. Consistent with the IBA annotation above. Reason: Redundant with IBA annotation but correctly inferred from domain composition. The COX4 domain family (Pfam PF02936) is specific to cytochrome c oxidase subunit IV, making this IEA inference sound.
GO:0045277 respiratory chain complex IV	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of the IBA annotation for the same GO term. This IEA annotation is from combined automated methods. Consistent with structural and phylogenetic evidence. Reason: Redundant with the IBA annotation but correctly inferred. COX4I1 is a well-established subunit of Complex IV.
GO:0005515 protein binding	IPI PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	MARK AS OVER ANNOTATED	Summary: PMID:23260140 (Mick et al. 2012, Cell) describes MITRAC complexes - early cytochrome c oxidase assembly intermediates. COX4I1 was found as a component of MITRAC complexes, interacting with MT-CO1 (UniProtKB:P00395). The WITH/FROM column shows the interactor is MT-CO1. This interaction represents a CIV assembly intermediate interaction between a nuclear- encoded subunit and the catalytic core subunit. Reason: The interaction between COX4I1 and MT-CO1 is a subunit-subunit interaction within Complex IV and during CIV assembly. Annotating this as generic "protein binding" is uninformative. The interaction is better captured by the part_of GO:0045277 (respiratory chain complex IV) annotation and could be more specifically annotated as part of Complex IV assembly. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates containing proteins required for normal mitochondrial translation and reveal assembly factors promoting biogenesis of human respiratory-chain complexes
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: PMID:25416956 (Rolland et al. 2014, Cell) is a large-scale proteome-wide Y2H interactome study. The WITH/FROM shows the interactor is SDCBP (O00560, syntenin-1). This is a high-throughput interaction without targeted validation for COX4I1 specifically. Reason: Generic "protein binding" from a large-scale Y2H screen. SDCBP (syntenin-1) is a PDZ domain-containing scaffolding protein primarily associated with cell surface signaling and exosomes. An interaction between the mitochondrial inner membrane protein COX4I1 and the cytoplasmic/membrane protein SDCBP is of uncertain biological significance and likely reflects the high false-positive rate of Y2H screens for proteins in different compartments. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: PMID:28514442 (Huttlin et al. 2017, Nature) is the BioPlex 2.0 large-scale AP-MS interactome study. The WITH/FROM shows the interactor is DBT (P11182, dihydrolipoamide branched chain transacylase). Both proteins are mitochondrial matrix-associated, so the interaction is at least compartment-consistent. Reason: Generic "protein binding" from a large-scale AP-MS screen. While both COX4I1 and DBT are mitochondrial proteins, DBT is a component of the branched-chain alpha-keto acid dehydrogenase complex, not Complex IV. The interaction may reflect co-purification from mitochondrial extracts rather than a specific functional interaction. "Protein binding" is uninformative regardless. Supporting Evidence: PMID:28514442 Here we present BioPlex 2.0 (Biophysical Interactions of ORFeome-derived complexes), which uses robust affinity purification-mass spectrometry methodology to elucidate protein interaction networks and co-complexes nucleated by more than 25% of protein-coding genes from the human genome
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: PMID:31515488 (Fragoza et al. 2019, Nat Commun) is a large-scale study of how genetic variants disrupt protein-protein interactions. The WITH/FROM shows interaction with SDCBP (O00560). Same interactor as the PMID:25416956 annotation above. This study primarily characterizes how SNVs affect known interactions from Y2H. Reason: Same reasoning as for PMID:25416956 - this is the same COX4I1-SDCBP interaction from Y2H screening. Generic "protein binding" is uninformative, and the biological relevance of a mitochondrial inner membrane protein interacting with the cytoplasmic scaffolding protein SDCBP is questionable. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: PMID:32814053 (Haenig et al. 2020, Cell Rep) is a neurodegenerative disease interactome mapping study. The WITH/FROM shows the interactor is KLF11 (O14901, Krueppel-like factor 11), a nuclear transcription factor. An interaction between a mitochondrial inner membrane protein and a nuclear transcription factor is biologically implausible. Reason: Generic "protein binding" from a disease-focused interactome screen. KLF11 is a nuclear Krueppel-like transcription factor involved in TGF-beta signaling. A direct physical interaction between COX4I1 (mitochondrial inner membrane) and KLF11 (nucleus) is not biologically plausible and likely represents a false positive from the high-throughput screen. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: PMID:33961781 (Huttlin et al. 2021, Cell) is the BioPlex 3.0 dual proteome-scale AP-MS interactome study. The GOA file shows two entries for this PMID - one with MT-CO1 (P00395) and one with DBT (P11182). The MT-CO1 interaction represents a genuine intra-complex interaction, while the DBT interaction is likely co-purification. Reason: Generic "protein binding" is uninformative even when the interaction (with MT-CO1) is biologically meaningful. The COX4I1-MT-CO1 interaction is a direct subunit-subunit contact within Complex IV, already captured by the part_of GO:0045277 annotation. The DBT interaction is likely co-purification from mitochondrial extracts. Supporting Evidence: PMID:33961781 Thousands of interactions assemble proteins into modules that impart spatial and functional organization to the cellular proteome
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Second entry from PMID:33961781 BioPlex 3.0 study, with interactor DBT (P11182, dihydrolipoamide branched chain transacylase). See previous entry for same PMID for general assessment. Reason: Same reasoning as above. Generic "protein binding" with DBT from large-scale AP-MS. DBT is a mitochondrial matrix enzyme of the BCKD complex, not a known functional partner of Complex IV. Likely co-purification artifact. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GO:0005739 mitochondrion	IEA GO_REF:0000107	ACCEPT	Summary: COX4I1 is imported to the mitochondrion where it is a subunit of Complex IV in the inner membrane. This broad localization is well supported by all evidence. Reason: Correct IEA annotation. COX4I1 is a mitochondrial protein by all lines of evidence - structural, biochemical, and computational. While more specific terms (inner membrane, Complex IV) exist and are also annotated, the broader mitochondrion annotation is acceptable.
GO:0005829 cytosol	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: COX4I1 is synthesized in the cytosol as a precursor with a mitochondrial transit peptide (residues 1-22), which is cleaved upon import. The mature protein resides in the mitochondrial inner membrane. Cytosolic localization is only transient during biosynthesis. Reason: While COX4I1 precursor is transiently in the cytosol during translation and before mitochondrial import, the functional protein resides in the mitochondrial inner membrane. This IEA annotation likely comes from Ensembl Compara transfer from mouse data where cytosolic detection may reflect the precursor form. The cytosol is not the functional location of COX4I1.
GO:0007584 response to nutrient	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation is transferred from rat COX4I1 (P10888) via Ensembl Compara. COX4I1 does have an allosteric ATP/ADP regulatory site that senses energy status, but "response to nutrient" is too vague and indirect to describe this regulatory function. Reason: While COX4I1 activity is modulated by cellular energy status (ATP/ADP ratio) and could indirectly respond to nutrient availability, this term is too broad and non-specific. The primary regulatory function of COX4I1 is allosteric inhibition by ATP, not a direct response to nutrients. This IEA transfer is over-annotation.
GO:0031966 mitochondrial membrane	IEA GO_REF:0000107	ACCEPT	Summary: COX4I1 is a mitochondrial inner membrane protein. The term "mitochondrial membrane" is a parent of "mitochondrial inner membrane" and is less specific but not wrong. Reason: Correct but less specific than the available inner membrane annotations. This IEA is acceptable as a broader localization term that is consistent with the more specific inner membrane annotations.
GO:0005739 mitochondrion	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation based on curation of immunofluorescence data (HPA). COX4I1 is detected in mitochondria by immunofluorescence in the Human Protein Atlas. Reason: Direct experimental evidence (immunofluorescence) confirming mitochondrial localization. Consistent with all other localization evidence.
GO:0006123 mitochondrial electron transport, cytochrome c to oxygen	NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: PMID:30030519 (Zong et al. 2018) reports the cryo-EM structure of the intact 14-subunit human Complex IV, which catalyzes electron transfer from cytochrome c to oxygen. COX4I1 is resolved as a structural subunit. NAS (Non-traceable Author Statement) from ComplexPortal. Reason: Correct annotation. The reference describes the complete structure of the complex that performs this process, and COX4I1 is an integral subunit. Redundant with IBA annotation but correctly attributed. Supporting Evidence: PMID:30030519 CIV is the terminal oxidase of the electron transport chain in mitochondria...It accepts electrons from cytochrome c to reduce the oxygen to water
GO:0031966 mitochondrial membrane	IDA PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: PMID:30030519 (Zong et al. 2018) provides cryo-EM structural evidence for COX4I1 in the mitochondrial inner membrane as part of Complex IV. ComplexPortal annotated this as IDA from the structural data. Reason: Correct localization, directly demonstrated by cryo-EM structure. The more specific term "mitochondrial inner membrane" (GO:0005743) would be preferable but this broader annotation from the structural study is acceptable. Supporting Evidence: PMID:30030519 we obtained the entire CIV structure containing 14 subunits
GO:0045333 cellular respiration	NAS PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidas...	ACCEPT	Summary: COX4I1 as a subunit of Complex IV participates in cellular respiration. Complex IV is the terminal enzyme of the respiratory chain, and cellular respiration encompasses the full OXPHOS pathway. This is a broad but correct process annotation from ComplexPortal. Reason: Correct biological process annotation. Complex IV is an essential component of cellular respiration. However, more specific terms (GO:0006123 mitochondrial electron transport, cytochrome c to oxygen) are also annotated and are more informative. This broader term is acceptable as a parent-level annotation. Supporting Evidence: PMID:30030519 Structure of the intact 14-subunit human cytochrome c oxidase.
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: PMID:34800366 (Morgenstern et al. 2021) is a quantitative high-confidence human mitochondrial proteome study. COX4I1 was identified as a high- confidence mitochondrial protein. HTP evidence from proteomics. Reason: High-throughput proteomics confirming mitochondrial localization. Consistent with all other evidence. Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context
GO:0045277 respiratory chain complex IV	IMP PMID:19393246 Knockdown of human COX17 affects assembly and supramolecular...	ACCEPT	Summary: PMID:19393246 (Oswald et al. 2009) investigates COX17 knockdown effects on CIV assembly. The study shows that COX17 knockdown affects CIV assembly and supramolecular organization, and COX4I1 was observed in assembly intermediates. The IMP annotation indicates COX4I1 is part of CIV based on mutant phenotype data. Reason: IMP evidence supporting COX4I1 as a component of Complex IV. The study demonstrates that perturbation of CIV assembly (via COX17 knockdown) affects COX4I1-containing complexes, supporting its membership in CIV. Supporting Evidence: PMID:19393246 COX17 siRNA knockdown affects activity and assembly of cytochrome c oxidase
GO:0005758 mitochondrial intermembrane space	TAS Reactome:R-HSA-9865412	ACCEPT	Summary: Reactome pathway R-HSA-9865412 describes TIMM21-mediated transport of COX4, COX5A, COX6C to the MT-CO1:MITRAC complex. The IMS annotation reflects the C-terminal domain of COX4I1 that extends into the IMS. Reason: TAS from Reactome. COX4I1 has an IMS-facing C-terminal domain (residues 125-169) as confirmed by UniProt topology annotations and cryo-EM structure. The annotation is technically correct. Supporting Evidence: file:human/COX4I1/COX4I1-uniprot.txt TOPO_DOM 125..169 /note="Mitochondrial intermembrane"
GO:0006119 oxidative phosphorylation	IEA GO_REF:0000041	ACCEPT	Summary: IEA annotation based on UniPathway vocabulary mapping (UPA00705). COX4I1 as a subunit of Complex IV directly participates in oxidative phosphorylation. Reason: Correct process annotation. Complex IV is part of the OXPHOS system. UniProt explicitly states "PATHWAY: Energy metabolism; oxidative phosphorylation." This IEA correctly captures that COX4I1 participates in oxidative phosphorylation. Supporting Evidence: file:human/COX4I1/COX4I1-uniprot.txt PATHWAY: Energy metabolism; oxidative phosphorylation
GO:0005739 mitochondrion	IDA PMID:26746385 Functional expression of choline transporter like-protein 1 ...	ACCEPT	Summary: PMID:26746385 (Iwao et al. 2016) is about choline transporter-like proteins in human brain microvascular endothelial cells. The paper found CTL1 and CTL2 expressed on plasma membrane and mitochondria. COX4I1 was likely used as a mitochondrial marker in this study, not the primary subject. Reason: IDA evidence for mitochondrial localization. Even though COX4I1 was likely used as a marker protein in this study, the localization result is correct and consistent with all other evidence. Supporting Evidence: PMID:26746385 Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells.
GO:0005743 mitochondrial inner membrane	ISS GO_REF:0000024	ACCEPT	Summary: ISS annotation based on manual transfer from mouse ortholog P19783. COX4I1 localizes to the inner mitochondrial membrane as confirmed by direct structural evidence in human. Reason: Correct localization. The ISS transfer from mouse is fully supported by direct human structural data (PMID:30030519) and UniProt annotation. Supporting Evidence: file:human/COX4I1/COX4I1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion inner membrane...Single-pass membrane protein
GO:0005739 mitochondrion	IDA PMID:15565177 A novel mitochondrial protein DIP mediates E2F1-induced apop...	ACCEPT	Summary: PMID:15565177 (Stanelle et al. 2005) describes DIP (KIAA0767), a novel mitochondrial protein. COX4I1 was likely used as a mitochondrial marker in localization studies. Reason: IDA evidence for mitochondrial localization, regardless of whether COX4I1 was a marker or target in this study. The localization is correct. Supporting Evidence: PMID:15565177 A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently of p53.
GO:0005515 protein binding	IPI PMID:26759378 The mammalian homologue of yeast Afg1 ATPase (lactation elev...	MARK AS OVER ANNOTATED	Summary: PMID:26759378 (Cesnekova et al. 2016) demonstrates that LACE1/AFG1L (Q8WV93), a mitochondrial AAA-ATPase, physically interacts with COX4I1 and mediates its degradation. This is a targeted, specific study showing that "LACE1...interacts physically with COX4 and COX5A subunits of complex IV." However, the annotation as generic "protein binding" does not capture the biological context of this interaction. Reason: While the LACE1-COX4I1 interaction is biologically meaningful (LACE1 mediates degradation of nuclear-encoded CIV subunits including COX4), annotating it as generic "protein binding" is uninformative. This interaction is part of a quality control pathway for mitochondrial protein homeostasis, not a core function of COX4I1 itself. Supporting Evidence: PMID:26759378 LACE1 mediates degradation of nuclear-encoded complex IV subunits COX4 (cytochrome c oxidase 4), COX5A and COX6A...the protein interacts physically with COX4 and COX5A subunits of complex IV and with mitochondrial inner-membrane protease YME1L
GO:0005515 protein binding	IPI PMID:26321642 MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Chec...	MARK AS OVER ANNOTATED	Summary: PMID:26321642 (Dennerlein et al. 2015) identifies MITRAC7 as a COX1-specific chaperone. COX4I1 was found in MITRAC complex intermediates along with MT-CO1 (P00395), SURF1 (Q15526), C12orf62 (Q8N5G0), and COX14 (Q9Y2R0). This represents a genuine CIV assembly intermediate interaction. Reason: Generic "protein binding" is uninformative. The interactions described are subunit-subunit contacts within CIV assembly intermediates, which are better captured by the part_of GO:0045277 and involvement in CIV assembly process annotations. Supporting Evidence: PMID:26321642 The MITRAC complex represents the central assembly intermediate during this process as it receives imported subunits and regulates mitochondrial translation of COX1 mRNA
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	ACCEPT	Summary: PMID:19946888 (Ghosh et al. 2010) defines the membrane proteome of NK cells using mass spectrometry. COX4I1 was identified in membrane fractions. The annotation to the very broad term "membrane" is correct but provides minimal information. Reason: Correct but very general. COX4I1 is a membrane protein (inner mitochondrial membrane). The broad term "membrane" adds little information beyond what is already captured by the more specific inner membrane annotations, but it is not wrong. Supporting Evidence: PMID:19946888 Defining the membrane proteome of NK cells.
GO:0005739 mitochondrion	HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated...	ACCEPT	Summary: PMID:20833797 (Zhao et al. 2011) is a phosphoproteomics study of functional mitochondria isolated from resting human muscle. COX4I1 was identified in the mitochondrial phosphoproteome. Reason: HDA evidence from mitochondrial proteomics confirming localization. Consistent with all other evidence. The study also identified phosphorylation sites in OXPHOS complexes, relevant to COX4I1's regulatory phosphorylation. Supporting Evidence: PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-163214	ACCEPT	Summary: Reactome pathway R-HSA-163214 (Electron transfer from reduced cytochrome c to molecular oxygen) places COX4I1 in the mitochondrial inner membrane as part of CIV. Reason: Correct TAS annotation from Reactome. COX4I1 is in the inner mitochondrial membrane as part of Complex IV, which catalyzes electron transfer from cytochrome c to oxygen.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9709406	ACCEPT	Summary: Reactome pathway R-HSA-9709406 (CO binds to Cytochrome c oxidase) places COX4I1 in the mitochondrial inner membrane. This pathway describes carbon monoxide binding to CIV. Reason: Correct TAS localization. COX4I1 is in the inner mitochondrial membrane as a CIV subunit.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865412	ACCEPT	Summary: Reactome pathway R-HSA-9865412 (TIMM21 carries COX4, COX5A, COX6C to MT-CO1:MITRAC) places COX4I1 in the inner membrane during CIV assembly. Reason: Correct TAS localization from CIV assembly pathway in Reactome.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865449	ACCEPT	Summary: Reactome pathway R-HSA-9865449 (Metallochaperone inserts Cu2+ into MT-CO1) places COX4I1 in the inner membrane during copper insertion step of CIV assembly. Reason: Correct TAS localization from CIV assembly pathway in Reactome.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865579	ACCEPT	Summary: Reactome pathway R-HSA-9865579 (MT-CO1 and MT-CO2 complexes associate, installing heme moieties) places COX4I1 in the inner membrane during CIV assembly. Reason: Correct TAS localization from CIV assembly pathway in Reactome.
GO:0005743 mitochondrial inner membrane	TAS Reactome:R-HSA-9865663	ACCEPT	Summary: Reactome pathway R-HSA-9865663 (MT-CO3, COX6A,B,7A and NDUFA4 bind to holo-MT-CO1,2 complex) places COX4I1 in the inner membrane during late CIV assembly. Reason: Correct TAS localization from CIV assembly pathway in Reactome.
GO:0004129 cytochrome-c oxidase activity	TAS PMID:2157630 Novel use of a chimpanzee pseudogene for chromosomal mapping...	ACCEPT	Summary: PMID:2157630 (Lomax et al. 1990) describes chromosomal mapping of human COX4 using a chimpanzee pseudogene. The paper identifies COX4I1 as a subunit of cytochrome c oxidase (EC 1.9.3.1) and maps the gene to chromosome 16. This is a TAS (Traceable Author Statement) annotation from the early characterization of the gene. For complex subunits, the qualifier should be "contributes_to" rather than "enables" since COX4I1 is a non-catalytic regulatory subunit. Reason: COX4I1 is a structural and regulatory subunit of CIV, which has cytochrome-c oxidase activity. The appropriate GO annotation pattern for non-catalytic complex subunits is "contributes_to" for complex-level molecular function. COX4I1 contributes to CIV activity through structural support, assembly, and allosteric regulation, though it does not itself catalyze the electron transfer reaction. The GOA file shows the qualifier as "enables" but this should ideally be "contributes_to" per GO annotation conventions for complex subunits. Supporting Evidence: PMID:2157630 subunit IV of cytochrome c oxidase (COX; EC 1.9.3.1) file:human/COX4I1/COX4I1-deep-research-falcon.md COX4-1 integrates matrix adenine nucleotide/PKA signals to adjust complex IV turnover to cellular energy state, supports cytochrome c docking via COX2 interactions, and participates in assembly and supercomplex formation
GO:0006091 generation of precursor metabolites and energy	TAS PMID:2157630 Novel use of a chimpanzee pseudogene for chromosomal mapping...	ACCEPT	Summary: Very broad biological process annotation. COX4I1 as part of Complex IV contributes to generation of precursor metabolites and energy through oxidative phosphorylation. However, this is an extremely general term that adds little specificity beyond the more precise OXPHOS and electron transport annotations already present. Reason: Correct but very broad. More specific process annotations (GO:0006123, GO:0006119, GO:0045333) are also present and are more informative. This annotation is technically correct as CIV drives proton pumping that powers ATP synthesis. Supporting Evidence: PMID:2157630 Novel use of a chimpanzee pseudogene for chromosomal mapping of human cytochrome c oxidase subunit IV.
GO:0005524 ATP binding	IDA PMID:21641552 Protein phosphorylation and prevention of cytochrome oxidase...	NEW	Summary: COX4I1 has a well-characterized ATP/ADP-binding allosteric site in its matrix-facing domain. ATP binding at high ATP/ADP ratios inhibits Complex IV activity. This has been demonstrated experimentally, notably by Acin-Perez et al. (2011, PMID:21641552) who showed that phosphorylation of Ser58 by PKA prevents ATP binding and relieves inhibition. The deep research review confirms "An ATP-binding site in COX4-1's matrix domain mediates allosteric inhibition of complex IV when ATP/ADP is high." Reason: ATP binding is a specific molecular function of COX4I1 that is not represented in the current GO annotation set. This is the basis of COX4I1's key regulatory function - allosteric inhibition of Complex IV at high ATP/ADP ratios. This is a subunit-specific MF annotation distinct from the complex-level cytochrome-c oxidase activity. Supporting Evidence: PMID:21641552 Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. file:human/COX4I1/COX4I1-deep-research-falcon.md An ATP-binding site in COX4-1's matrix domain mediates allosteric inhibition of complex IV when ATP/ADP is high; phosphorylation of Ser58 by intramitochondrial PKA (sAC-cAMP-PKA axis) prevents ATP binding and relieves inhibition, functioning as a rapid bioenergetic switch
GO:1904959 regulation of cytochrome-c oxidase activity	IDA PMID:21641552 Protein phosphorylation and prevention of cytochrome oxidase...	NEW	Summary: COX4I1 is the primary regulatory subunit of Complex IV, mediating allosteric feedback inhibition through its ATP/ADP binding site and through PKA-dependent phosphorylation at Ser58. This regulatory function is the defining characteristic that distinguishes COX4I1 from purely structural CIV subunits. "Regulation of cytochrome-c oxidase activity" (GO:1904959) precisely captures this core function. Reason: This is a key missing annotation. COX4I1's regulatory function through allosteric ATP binding and PKA phosphorylation is its primary distinguishing role. The deep research review emphasizes this: "noncatalytic, COX4-1 regulates complex IV turnover and assembly... integrates metabolic signals via adenine nucleotide binding." Supporting Evidence: PMID:21641552 Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. file:human/COX4I1/COX4I1-deep-research-falcon.md COX4-1 modulates this pacemaker step of the electron transport chain through allosteric control...phosphorylation of Ser58 by intramitochondrial PKA...prevents ATP binding and relieves inhibition
GO:0033617 mitochondrial respiratory chain complex IV assembly	TAS PMID:23260140 MITRAC links mitochondrial protein translocation to respirat...	NEW	Summary: COX4I1 participates in early CIV assembly intermediates (MITRAC complexes). It is one of the first nuclear-encoded subunits to be incorporated during assembly (COX4-COX5A module). Multiple publications demonstrate COX4I1's role in CIV assembly, including PMID:23260140 (MITRAC complexes) and PMID:26321642 (MITRAC7 assembly checkpoint). This process is not currently annotated for COX4I1. Reason: COX4I1 is a key participant in CIV assembly. The deep research review states "COX4 participates in early assembly modules (COX4-COX5A)." Multiple Reactome pathways describe COX4I1's role in assembly steps. This is a core biological process annotation that is missing from the current set. Supporting Evidence: PMID:23260140 we report a comprehensive dissection of early cytochrome c oxidase assembly intermediates file:human/COX4I1/COX4I1-deep-research-falcon.md COX4 participates in early assembly modules (COX4-COX5A) and contributes to respirasome (CI-CIII2-CIV) formation

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

📄 View Raw YAML