LYRM7 (LYR motif-containing protein 7; also MZM1L/C5orf31) is a small mitochondrial-matrix LYR-family assembly chaperone for respiratory Complex III (cytochrome bc1 / ubiquinol-cytochrome c reductase). It acts as a dedicated chaperone for the Rieske iron-sulfur protein UQCRFS1, binding and stabilising UQCRFS1 in the mitochondrial matrix prior to insertion of its [2Fe-2S] cluster and the subunit's translocation and incorporation into the late Complex III dimeric intermediate in the inner membrane. Its LYR motif recruits the Fe-S transfer cochaperone HSC20 (HSCB), coupling the UQCRFS1-LYRM7 intermediate to the ISCU-HSPA9-HSC20 cluster-delivery machinery. LYRM7 is non-catalytic and is the human ortholog of yeast Mzm1. Loss-of-function variants cause mitochondrial complex III deficiency, nuclear type 8 (a leukoencephalopathy).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005759 mitochondrial matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) propagation placing LYRM7 in the mitochondrial matrix, where it acts as a chaperone. This is directly confirmed experimentally: LYRM7 binds and stabilises UQCRFS1 within the mitochondrial matrix. Reason: The matrix location is the site of LYRM7's chaperone activity and is supported by direct experimental evidence (IDA, PMID:23168492) and the UniProt subcellular location, in addition to this phylogenetic inference. is_active_in is appropriate for the compartment where it chaperones UQCRFS1. Supporting Evidence: PMID:23168492 binding to this subunit within the file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0034551 mitochondrial respiratory chain complex III assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) inference that LYRM7 is involved in Complex III assembly. This is the core biological process of the gene and is strongly supported experimentally. Reason: LYRM7 is a bona fide Complex III assembly factor mediating the UQCRFS1/Rieske Fe-S protein incorporation step. This is the precise, well-evidenced core BP and is consistent across IBA, IDA (PMID:23168492), IEA and Reactome TAS annotations. Supporting Evidence: PMID:23168492 LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 |
| GO:0044183 protein folding chaperone | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) assignment of a protein folding chaperone molecular function. LYRM7 is a non-catalytic chaperone that binds and stabilises (holds) its client UQCRFS1, so a chaperone MF is the correct, most informative non-catalytic molecular function. Reason: The chaperone MF is directly supported: LYRM7 works as a UQCRFS1 chaperone, binding and stabilising the Rieske Fe-S protein prior to its incorporation into Complex III (PMID:23168492). This is the appropriate MF for this non-enzymatic assembly factor and is retained as the core molecular function; no catalytic activity should be assigned. Supporting Evidence: PMID:23168492 works as a human Rieske file:human/LYRM7/LYRM7-uniprot.txt Assembly factor required for Rieske Fe-S protein UQCRFS1 |
| GO:0005739 mitochondrion | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to the mitochondrion, based on the Complex1_LYR domain family. Correct but less specific than the matrix localisation. Reason: Mitochondrial localisation is correct and well supported; this is simply a broader (parent) location than the experimentally established mitochondrial matrix. Retained as a valid, if general, CC annotation. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation to the mitochondrial matrix from the UniProt Swiss-Prot subcellular location vocabulary mapping. Matches the curated UniProt location and experimental evidence. Reason: Consistent with the experimentally determined (IDA, PMID:23168492) and curated UniProt matrix location where LYRM7 chaperones UQCRFS1. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0006457 protein folding | IEA GO_REF:0000108 | ACCEPT | Summary: Inter-ontology (logical) inference of a protein folding BP from the protein folding chaperone MF (GO:0044183). Consistent with LYRM7's role in stabilising/holding UQCRFS1. Reason: This is a sound, if general, logical consequence of the chaperone MF. LYRM7 stabilises its unfolded/apo client UQCRFS1, which falls under protein folding. It is broader than the specific Complex III assembly BP but not incorrect. Kept as non-core context; the precise core BP is mitochondrial respiratory chain complex III assembly. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt stabilizing it prior to its translocation and insertion into the late |
| GO:0034551 mitochondrial respiratory chain complex III assembly | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to Complex III assembly, based on the LYRM7-specific InterPro family (IPR045298). Correct and matches experimental evidence. Reason: The LYRM7/MZM1-LYRM7 family signature reliably predicts a Complex III assembly-factor role, which is experimentally confirmed. This is the core BP. Supporting Evidence: PMID:23168492 LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 |
| GO:0005515 protein binding | IPI PMID:24606901 Cochaperone binding to LYR motifs confers specificity of iro... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) capturing a physical interaction between LYRM7 and HSC20/HSCB (UniProt Q8IWL3), the Fe-S cluster transfer cochaperone. This is a real and functionally meaningful interaction (LYRM7's LYR motif is an HSC20 binding site), but the GO term "protein binding" is uninformative. Reason: Bare protein binding (GO:0005515) conveys no specific molecular function. The underlying LYRM7-HSC20 interaction is genuine and biologically important (it couples the UQCRFS1-LYRM7 intermediate to the Fe-S transfer machinery), so this is not removed; but the term is retained only as an uninformative over-annotation. The informative MF is the chaperone activity (GO:0044183). Supporting Evidence: PMID:24606901 SDHAF1 and LYRM7, respectively, are HSC20 binding partners |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) capturing a physical interaction between LYRM7 and UQCRFS1 (P47985) reported in a large-scale mitochondrial protein interaction map. UQCRFS1 is the physiological client of LYRM7, so the interaction is correct, but "protein binding" is uninformative. Reason: The LYRM7-UQCRFS1 interaction is the core, well-established relationship of this gene, but bare GO:0005515 does not capture the chaperone function. Retained as an uninformative over-annotation rather than removed. Supporting Evidence: PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory |
| GO:0005515 protein binding | IPI PMID:28380382 A Single Adaptable Cochaperone-Scaffold Complex Delivers Nas... | MARK AS OVER ANNOTATED | Summary: IPI (IntAct) capturing physical interactions of LYRM7 with UQCRFS1 (P47985) and with HSC20/HSCB (Q8IWL3). Both are physiologically central: the UQCRFS1-LYRM7 intermediate recruits HSC20 via LYRM7's LYR motif to deliver the [2Fe-2S] cluster to UQCRFS1. Reason: The interactions are real and mechanistically important, but bare protein binding is uninformative and does not capture the chaperone/assembly-factor MF. Retained as an over-annotation rather than removed. Supporting Evidence: PMID:28380382 direct binding of the co-chaperone HSC20 to the LYR (Leucine, Tyrosine, Arginine) consensus sequence of LYRM7 was required for recruitment of the Fe-S transfer complex to the LYRM7-UQCRFS1 assembly intermediate |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI from the HuRI binary (yeast two-hybrid) reference interactome mapping LYRM7 to SAT1 (P21673, spermidine/spermine N1-acetyltransferase). SAT1 has no known mitochondrial or Complex III role; this is most likely a non-physiological binary-screen hit. Reason: Bare protein binding is uninformative, and this particular partner (SAT1) is not a plausible physiological interactor of a mitochondrial-matrix CIII assembly chaperone. Per curation policy, an experimental IPI is not removed on the basis of an incomplete assessment; it is marked as an uninformative (and here likely non-physiological) over-annotation. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI (BioPlex) capturing a physical interaction between LYRM7 and UQCRFS1 (P47985) in a proteome-scale affinity-purification interactome. Consistent with the core LYRM7-UQCRFS1 client relationship. Reason: Correct interaction with the physiological client UQCRFS1, but bare GO:0005515 is uninformative. Retained as an over-annotation rather than removed; the chaperone MF (GO:0044183) captures the function. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI capturing a physical interaction between LYRM7 and UQCRFS1 (P47985) in a large-scale cell-map / structural-functional genomics interactome. Consistent with the core client relationship. Reason: Correct interaction with UQCRFS1 but bare protein binding is uninformative. Retained as an over-annotation; the informative MF is the chaperone activity. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics |
| GO:0034551 mitochondrial respiratory chain complex III assembly | TAS Reactome:R-HSA-9865881 | ACCEPT | Summary: Reactome (TAS) annotation placing LYRM7 in the Complex III assembly pathway. Matches the core, experimentally supported BP. Reason: Reactome curates LYRM7 as a Complex III assembly factor (the UQCRFS1/Rieske protein binds and is stabilised by LYRM7). This is the correct core BP. Supporting Evidence: PMID:23168492 LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput annotation of LYRM7 to the mitochondrion from a quantitative high-confidence human mitochondrial proteome. Consistent with the curated matrix localisation. Reason: Independent proteomic support for mitochondrial localisation; broader than the specific matrix location but correct. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0044183 protein folding chaperone | TAS Reactome:R-HSA-9866253 | ACCEPT | Summary: Reactome (TAS) assignment of the protein folding chaperone MF, corresponding to the reaction in which apo-UQCRFS1 binds and is stabilised by LYRM7. Matches the core chaperone function. Reason: Reactome curates LYRM7 as the chaperone that binds and stabilises apo-UQCRFS1 in the matrix, the correct non-catalytic MF for this assembly factor. Core molecular function. Supporting Evidence: PMID:23168492 works as a human Rieske |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9866253 | ACCEPT | Summary: Reactome (TAS) localisation of LYRM7 to the mitochondrial matrix, the compartment where apo-UQCRFS1 binds LYRM7. Matches experimental and curated localisation. Reason: Consistent with the experimentally established matrix location where LYRM7 chaperones UQCRFS1. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9866272 | ACCEPT | Summary: Reactome (TAS) localisation of LYRM7 to the mitochondrial matrix, associated with the reaction inserting the [2Fe-2S] cluster into UQCRFS1 as part of the UQCRFS1:LYRM7 complex. Reason: Consistent with the matrix location where the LYRM7-UQCRFS1 intermediate recruits the Fe-S transfer machinery for cluster insertion. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0005515 protein binding | IPI PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | MARK AS OVER ANNOTATED | Summary: IPI (UniProt) capturing the physical interaction between LYRM7 and UQCRFS1 (P47985) from the primary characterisation paper, in which LYRM7 was shown to bind and stabilise the Rieske Fe-S protein. This is the defining, physiological interaction of LYRM7. Reason: The LYRM7-UQCRFS1 interaction is the core relationship establishing LYRM7 as the UQCRFS1 chaperone, so it is not removed; however, bare protein binding (GO:0005515) is uninformative and does not capture the chaperone MF. The chaperone activity (GO:0044183) is the informative MF that should represent this function. Supporting Evidence: PMID:23168492 works as a human Rieske |
| GO:0005759 mitochondrial matrix | IDA PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | ACCEPT | Summary: Direct experimental (IDA) localisation of LYRM7 to the mitochondrial matrix from the primary characterisation study. This is the strongest evidence for the core localisation. Reason: LYRM7 was experimentally shown to reside in and act within the mitochondrial matrix, where it binds and stabilises UQCRFS1. Core CC annotation. Supporting Evidence: PMID:23168492 binding to this subunit within the file:human/LYRM7/LYRM7-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix |
| GO:0031966 mitochondrial membrane | IDA PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | KEEP AS NON CORE | Summary: Direct experimental (IDA) detection of a pool of LYRM7 associated with the mitochondrial membrane, consistent with its transient association with the membrane-embedded late Complex III dimeric intermediate during UQCRFS1 insertion. Reason: Membrane association is a real but secondary/transient aspect of LYRM7 function: its primary site of action is the matrix, where it chaperones UQCRFS1; the membrane pool reflects delivery of UQCRFS1 to the inner-membrane CIII intermediate. Kept but marked non-core relative to the matrix localisation. Supporting Evidence: file:human/LYRM7/LYRM7-uniprot.txt stabilizing it prior to its translocation and insertion into the late |
| GO:0034551 mitochondrial respiratory chain complex III assembly | IDA PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | ACCEPT | Summary: Direct experimental (IDA) evidence that LYRM7 is required for the UQCRFS1 insertion step of Complex III assembly. This is the definitive experimental support for the core BP. Reason: The primary study established LYRM7 as a Complex III assembly factor acting at the UQCRFS1 incorporation step; this is the core, best-supported biological process. Supporting Evidence: PMID:23168492 LYRM7/MZM1L is a novel human CIII assembly factor involved in the UQCRFS1 |
| GO:0045333 cellular respiration | IDA PMID:23168492 LYRM7/MZM1L is a UQCRFS1 chaperone involved in the last step... | MARK AS OVER ANNOTATED | Summary: IDA annotation to cellular respiration, based on the observation that loss of LYRM7 impairs Complex III activity and hence respiration. LYRM7 is an assembly factor, not itself a respiratory-chain component; its effect on respiration is indirect (via enabling functional Complex III). Reason: LYRM7 does not itself carry out or directly participate in respiration; it enables assembly of Complex III, whose activity is required for respiration. The precise, mechanistically accurate BP is mitochondrial respiratory chain complex III assembly (GO:0034551). Cellular respiration is an over-annotation capturing a downstream consequence rather than LYRM7's direct role. Not removed (experimental annotation) but flagged as over-annotated. Supporting Evidence: PMID:23168492 which enables formation of the mature and functional CIII |
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Download this section (compressed HTML)Q: Does LYRM7 act purely as a holdase that stabilises apo-UQCRFS1, or does it also actively template/position UQCRFS1 for [2Fe-2S] cluster receipt and membrane insertion?
Experiment: Reconstitute the UQCRFS1-LYRM7 intermediate with the HSC20-HSPA9-ISCU Fe-S transfer complex in vitro to determine the minimal components and the order of cluster insertion versus membrane insertion of UQCRFS1.
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