LYRM4 (also known as ISD11) is a small LYR motif-containing protein that serves as an essential non-catalytic stabilizing subunit of the cysteine desulfurase NFS1 in the mitochondrial iron-sulfur cluster (ISC) assembly machinery. LYRM4 forms a heterodimer with mitochondrial acyl carrier protein (NDUFAB1/ACP) and together they stabilize NFS1 and regulate its cysteine desulfurase activity. The core ISC assembly complex consists of NFS1-LYRM4-NDUFAB1-ISCU, with frataxin (FXN) serving as an allosteric activator and FDX2/FDXR providing reducing equivalents. LYRM4 contains conserved alpha-helices that form a hydrophobic tunnel accommodating the acyl chain of phosphopantetheinylated NDUFAB1, linking mitochondrial fatty acid synthesis to Fe-S cluster biogenesis. Mutations in LYRM4 cause combined oxidative phosphorylation deficiency 19 (COXPD19), characterized by respiratory distress, hypotonia, and lactic acidosis. While primarily mitochondrial, NFS1 and LYRM4 have also been detected in the nucleus and cytosol where NFS1 participates in molybdenum cofactor biosynthesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: LYRM4/ISD11 is a mitochondrial protein that functions as part of the core ISC assembly complex in the mitochondrial matrix. Multiple studies confirm mitochondrial localization via immunofluorescence and subcellular fractionation (PMID:17331979, PMID:23593335). The IBA annotation is phylogenetically well-supported across eukaryotes. Reason: Mitochondrial localization is the primary site of LYRM4 function as a component of the ISC assembly complex. This is well-established by experimental evidence. Supporting Evidence: PMID:17331979 Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria. PMID:23593335 NFS1 and ISD11 are present in mitochondria and in the nucleus file:human/LYRM4/LYRM4-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0016226 iron-sulfur cluster assembly | IBA GO_REF:0000033 | ACCEPT | Summary: LYRM4 is essential for iron-sulfur cluster assembly as a stabilizing factor for NFS1 cysteine desulfurase. ISD11 depletion leads to decline of the NFS1/ISCU complex and decreased aconitase activity (PMID:17331979). The IBA annotation correctly captures this core biological process. Reason: Iron-sulfur cluster assembly is the primary biological process in which LYRM4 participates. This is well-supported by experimental evidence showing that ISD11 depletion impairs Fe-S cluster biogenesis. Supporting Evidence: PMID:17331979 Upon ISD11 depletion by siRNA in HEK293T cells, the amount of the Nfs1/ISCU protein complex declined, as did the activity of the iron-sulfur cluster enzyme aconitase |
| GO:0005198 structural molecule activity | IBA GO_REF:0000033 | ACCEPT | Summary: LYRM4/ISD11 provides structural stabilization of NFS1. Crystallographic studies show that ISD11 forms the dimeric core of the cysteine desulfurase complex with its pair of subunits, explaining its critical structural role (PMID:28634302). The IBA annotation is supported by structural evidence. Reason: Structural molecule activity accurately describes LYRM4's role in stabilizing NFS1 within the ISC assembly complex. Structural studies confirm that ISD11 subunits form the architectural core of the complex. Supporting Evidence: PMID:28634302 the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies |
| GO:1990221 L-cysteine desulfurase complex | IBA GO_REF:0000033 | ACCEPT | Summary: LYRM4 is an integral component of the L-cysteine desulfurase complex (NFS1-ISD11-ACP). Crystal structures confirm LYRM4 is part of this complex (PMID:29097656, PMID:28634302, PMID:31664822). Reason: This is the correct cellular component annotation for LYRM4's participation in the cysteine desulfurase complex. Supporting Evidence: PMID:28634302 In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP) PMID:31664822 Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization of LYRM4 has been experimentally demonstrated along with NFS1 (PMID:23593335). This IEA annotation is consistent with experimental findings. Reason: The IEA annotation is supported by experimental evidence from subcellular fractionation and fluorescence microscopy showing NFS1 and ISD11 in the nucleus. Supporting Evidence: PMID:23593335 NFS1 and ISD11 are present in mitochondria and in the nucleus |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: This IEA annotation duplicates the IBA annotation for mitochondrion. Both are correct and supported by strong experimental evidence. Reason: Mitochondrial localization is the primary site of LYRM4 function. This IEA annotation is consistent with experimental evidence. Supporting Evidence: PMID:17331979 Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria. |
| GO:0016226 iron-sulfur cluster assembly | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation from InterPro is consistent with the IBA annotation and experimental evidence for LYRM4's role in iron-sulfur cluster assembly. Reason: The annotation is correct and well-supported by domain analysis and experimental evidence. Supporting Evidence: PMID:17331979 Upon ISD11 depletion by siRNA in HEK293T cells, the amount of the Nfs1/ISCU protein complex declined, as did the activity of the iron-sulfur cluster enzyme aconitase |
| GO:0005515 protein binding | IPI PMID:26342079 Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcom... | MARK AS OVER ANNOTATED | Summary: This annotation captures LYRM4 interaction with NFS1. However, GO:0005515 protein binding is uninformative. The molecular adaptor activity annotation (GO:0060090) better captures LYRM4's function. Reason: Protein binding is too generic and uninformative. LYRM4's binding to NFS1 is better captured by more specific annotations such as molecular adaptor activity (GO:0060090) and structural molecule activity (GO:0005198). Supporting Evidence: PMID:26342079 2015 Sep 4. Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19. |
| GO:0005515 protein binding | IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat... | MARK AS OVER ANNOTATED | Summary: Protein binding annotation from mitochondrial protein interaction mapping study. Too generic to be informative. Reason: Protein binding is uninformative. The specific function of LYRM4 in binding NFS1 and ACP is better captured by molecular adaptor activity and structural molecule activity annotations. Supporting Evidence: PMID:27499296 2016 Aug 4. Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Generic protein binding annotation from interactome study. Uninformative. Reason: Protein binding is too generic. More specific MF annotations exist for LYRM4. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IEA GO_REF:0000107 | ACCEPT | Summary: LYRM4 is a component of the mitochondrial [2Fe-2S] assembly complex as part of the NFS1-ISD11-ACP-ISCU core complex. This IEA annotation from Ensembl Compara is well-supported by experimental structures. Reason: This is accurate. LYRM4 is part of the core ISC assembly complex that synthesizes [2Fe-2S] clusters on ISCU. Supporting Evidence: PMID:31101807 The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: This annotation from HPA immunofluorescence suggests localization to nuclear bodies. While nuclear localization of LYRM4 has been shown (PMID:23593335), specific localization to nuclear bodies is less well characterized. The functional significance of nuclear body localization is unclear. Reason: Nuclear localization of LYRM4 has experimental support, but its localization specifically to nuclear bodies and the functional significance thereof is less clear. The core function of LYRM4 is mitochondrial. Supporting Evidence: PMID:23593335 NFS1 and ISD11 are present in mitochondria and in the nucleus |
| GO:0005739 mitochondrion | NAS PMID:27519411 Architecture of the Human Mitochondrial Iron-Sulfur Cluster ... | ACCEPT | Summary: NAS annotation for mitochondrial localization from the Complex Portal paper on mitochondrial ISC assembly machinery architecture. Reason: Mitochondrial localization is well-established for LYRM4. Supporting Evidence: PMID:17331979 Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria. PMID:27519411 Epub 2016 Aug 12. Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery. |
| GO:0016226 iron-sulfur cluster assembly | NAS PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: NAS annotation from the structural study of the mitochondrial Fe/S cluster synthesis complex. This paper provides crystal structures of NFS1-ISD11-ACP complexes. Reason: Iron-sulfur cluster assembly is the core biological process for LYRM4. Supporting Evidence: PMID:29097656 De novo Fe/S cluster synthesis occurs on the mitochondrial scaffold protein ISCU and requires cysteine desulfurase NFS1, ferredoxin, frataxin, and the small factors ISD11 and ACP |
| GO:0060090 molecular adaptor activity | IDA PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpect... | ACCEPT | Summary: LYRM4 functions as a molecular adaptor bridging NFS1 and acyl-ACP. The crystal structure reveals that ISD11 subunits form the core of the complex and mediate interactions between NFS1 and ACP (PMID:28634302). This is a more informative MF annotation than protein binding. Reason: Molecular adaptor activity accurately describes LYRM4's role in bridging NFS1 and ACP within the cysteine desulfurase complex. Supporting Evidence: PMID:28634302 The structure also reveals the 4'-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. PMID:31664822 The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. |
| GO:0005198 structural molecule activity | IDA PMID:28634302 Structure of human Fe-S assembly subcomplex reveals unexpect... | ACCEPT | Summary: LYRM4 provides structural stabilization for NFS1. The crystal structure shows that ISD11 subunits form the dimeric core of the cysteine desulfurase complex (PMID:28634302). Reason: Structural molecule activity is appropriate for LYRM4's role in stabilizing NFS1 within the ISC complex. Supporting Evidence: PMID:28634302 a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: HTP annotation from quantitative mitochondrial proteome study. Consistent with established mitochondrial localization. Reason: Mitochondrial localization is the primary site of LYRM4 function. Supporting Evidence: PMID:17331979 Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria. PMID:34800366 Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. |
| GO:0005634 nucleus | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: IDA annotation for nuclear localization from subcellular fractionation and microscopy study. Reason: Nuclear localization has been demonstrated experimentally, though the mitochondrial function is the primary role. Supporting Evidence: PMID:23593335 NFS1 and ISD11 are present in mitochondria and in the nucleus |
| GO:0005739 mitochondrion | IDA PMID:23593335 The L-cysteine desulfurase NFS1 is localized in the cytosol ... | ACCEPT | Summary: IDA annotation for mitochondrial localization from subcellular fractionation and microscopy study. Reason: Mitochondrial localization is well-established by this and multiple other studies. Supporting Evidence: PMID:23593335 NFS1 and ISD11 are present in mitochondria and in the nucleus |
| GO:0005515 protein binding | IPI PMID:31664822 Structure of the Human ACP-ISD11 Heterodimer. | MARK AS OVER ANNOTATED | Summary: This annotation captures LYRM4 interaction with NDUFAB1 (ACP) from the ACP-ISD11 heterodimer structure paper. However, protein binding is uninformative. Reason: Protein binding is too generic. The interaction with ACP is better captured by the molecular adaptor activity and structural molecule activity annotations. Supporting Evidence: PMID:31664822 Epub 2019 Nov 8. Structure of the Human ACP-ISD11 Heterodimer. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:31664822 Structure of the Human ACP-ISD11 Heterodimer. | ACCEPT | Summary: LYRM4 participates in [2Fe-2S] cluster assembly as part of the ACP-ISD11 heterodimer that stabilizes NFS1 and enables cluster synthesis on ISCU. Reason: This is a more specific biological process term than iron-sulfur cluster assembly and accurately captures LYRM4's role in de novo [2Fe-2S] cluster synthesis. Supporting Evidence: PMID:31664822 the NFS1/ACP-ISD11 core complex was activated by frataxin and ISCU proteins |
| GO:0044572 [4Fe-4S] cluster assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS annotation for [4Fe-4S] cluster assembly based on orthology to mouse LYRM4. The core ISC complex primarily synthesizes [2Fe-2S] clusters which are then used by downstream factors (ISCA1, ISCA2, NFU1) to assemble [4Fe-4S] clusters. Reason: LYRM4's direct role is in [2Fe-2S] cluster assembly on ISCU. The [4Fe-4S] cluster assembly is a downstream process that depends on the [2Fe-2S] clusters produced by the core ISC complex. LYRM4 acts upstream of [4Fe-4S] assembly rather than directly participating in it. Supporting Evidence: PMID:31101807 The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex |
| GO:0005515 protein binding | IPI PMID:18650437 A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a... | MARK AS OVER ANNOTATED | Summary: This annotation captures LYRM4 interaction with NFS1 from a study on NFS1 role in molybdenum cofactor biosynthesis. Protein binding is uninformative. Reason: Protein binding is too generic. The NFS1 interaction is better captured by molecular adaptor activity and structural molecule activity annotations. Supporting Evidence: PMID:18650437 Epub 2008 Jul 23. A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. |
| GO:0005739 mitochondrion | IDA PMID:17331979 Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU... | ACCEPT | Summary: IDA annotation for mitochondrial localization from the foundational study on ISD11 interaction with frataxin and NFS1/ISCU complex. Reason: This is strong experimental evidence for mitochondrial localization from the paper that first characterized ISD11 function in mammals. Supporting Evidence: PMID:17331979 Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria. |
| GO:0044571 [2Fe-2S] cluster assembly | IDA PMID:17331979 Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU... | ACCEPT | Summary: IDA annotation for [2Fe-2S] cluster assembly based on siRNA knockdown experiments showing that ISD11 depletion leads to decreased aconitase activity. Reason: This is appropriate experimental evidence for LYRM4's role in Fe-S cluster assembly. Supporting Evidence: PMID:17331979 Upon ISD11 depletion by siRNA in HEK293T cells, the amount of the Nfs1/ISCU protein complex declined, as did the activity of the iron-sulfur cluster enzyme aconitase |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IDA PMID:31101807 Structure of the human frataxin-bound iron-sulfur cluster as... | ACCEPT | Summary: IDA annotation from the cryo-EM structure of the human frataxin-bound ISC assembly complex. This structure directly shows LYRM4/ISD11 as part of the NFS1-ISD11-ACP-ISCU-FXN complex. Reason: Structural evidence directly demonstrates LYRM4 is a component of the mitochondrial [2Fe-2S] assembly complex. Supporting Evidence: PMID:31101807 The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix, is a five-protein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. |
| GO:0042803 protein homodimerization activity | IDA PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | ACCEPT | Summary: LYRM4 has been shown to homodimerize within the ISC complex. Crystal structures show the (NFS1-ISD11-ACP)2 complex contains two copies of ISD11 (PMID:29097656). Reason: Homodimerization of LYRM4/ISD11 is structurally demonstrated and functionally relevant for complex assembly. Supporting Evidence: PMID:29097656 Crystal structures of (NFS1-ISD11-ACP)2 and (NFS1-ISD11-ACP-ISCU)2 complexes |
| GO:0042803 protein homodimerization activity | IDA PMID:34824239 N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synth... | ACCEPT | Summary: Homodimerization annotation from the study on ISCU2 dimerization triggering [2Fe-2S] cluster synthesis, which includes crystal structures of the NFS1-ISD11-ACP-ISCU2 complex. Reason: The crystal structures confirm LYRM4 homodimerization within the ISC complex. Supporting Evidence: PMID:34824239 we crystallized the dimeric (NIAU2)2 complex...NFS1 subunits are depicted in orange and yellow, ISD11 in purple and magenta |
| GO:0005515 protein binding | IPI PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S ... | MARK AS OVER ANNOTATED | Summary: Protein binding annotation from the structural study. Captures interaction with NFS1 and ISCU. However, protein binding is uninformative. Reason: Protein binding is too generic. The specific interactions are better captured by molecular adaptor activity and homodimerization activity annotations. Supporting Evidence: PMID:29097656 Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. |
| GO:0099128 mitochondrial [2Fe-2S] assembly complex | IDA PMID:21298097 Mammalian frataxin: an essential function for cellular viabi... | ACCEPT | Summary: IDA annotation from the study showing LYRM4 is part of the preformed ISCU/NFS1/ISD11 complex that frataxin binds for Fe-S cluster assembly. Reason: This study provides direct evidence that LYRM4/ISD11 is a component of the Fe-S cluster assembly complex. Supporting Evidence: PMID:21298097 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362408 | ACCEPT | Summary: TAS annotation from Reactome pathway for [2Fe-2S] cluster assembly. The ISC machinery operates in the mitochondrial matrix. Reason: Mitochondrial matrix is the correct sub-compartment localization for LYRM4 function in the ISC assembly machinery. Supporting Evidence: PMID:31101807 The core machinery for de novo biosynthesis of iron-sulfur clusters (ISC), located in the mitochondria matrix |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1362416 | ACCEPT | Summary: TAS annotation from Reactome pathway for frataxin binding iron. Consistent with mitochondrial matrix localization of the ISC complex. Reason: Mitochondrial matrix localization is correct for LYRM4. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9854984 | ACCEPT | Summary: TAS annotation from Reactome pathway for Fe-S cluster transfer to SDHB. Reason: Mitochondrial matrix localization is correct for LYRM4. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-9866272 | ACCEPT | Summary: TAS annotation from Reactome pathway for [2Fe-2S] insertion into UQCRFS1. Reason: Mitochondrial matrix localization is correct for LYRM4. |
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Download this section (compressed HTML)Q: Is LYRM4 required for NFS1 function in the nucleus/cytosol, or only in mitochondria?
Q: What is the functional significance of nuclear LYRM4 localization?
Q: How does the acylation state of NDUFAB1/ACP regulate LYRM4-NFS1 complex activity?
Experiment: Conditional knockout of LYRM4 in different cellular compartments to assess compartment-specific functions
Experiment: Mass spectrometry analysis of LYRM4 interactome in nuclear vs mitochondrial fractions
Experiment: Structure determination of cytosolic NFS1-LYRM4 complex if it exists
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