Existing Annotations Review

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.

Core Functions

LYRM4/ISD11 is an essential non-catalytic subunit that provides structural stabilization for NFS1 cysteine desulfurase. Crystal structures show that ISD11 subunits form the dimeric core of the cysteine desulfurase complex (PMID:28634302). ISD11 depletion leads to decline of the NFS1/ISCU complex (PMID:17331979).

Molecular Function:

structural molecule activity

Directly Involved In:

[2Fe-2S] cluster assembly

Cellular Locations:

mitochondrial matrix

In Complex:

L-cysteine desulfurase complex

LYRM4 functions as a molecular adaptor bridging NFS1 and acyl-ACP (NDUFAB1). The hydrophobic core of ISD11 accommodates the phosphopantetheine-acyl chain of ACP, linking mitochondrial fatty acid synthesis to Fe-S cluster biogenesis (PMID:28634302, PMID:31664822).

Molecular Function:

molecular adaptor activity

Directly Involved In:

iron-sulfur cluster assembly

Cellular Locations:

mitochondrial matrix

In Complex:

mitochondrial [2Fe-2S] assembly complex

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:17331979

Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones.

ISD11 co-localizes with frataxin and mitochondria

"Immunofluorescence analysis demonstrated that ISD11 co-localized with both frataxin and with mitochondria."
ISD11 depletion causes decline of NFS1/ISCU complex and aconitase activity

"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"
Frataxin-ISD11 interaction is nickel-dependent

"The frataxin/ISD11 interaction was also decreased by the chelator EDTA, and was increased by supplementation with nickel but not other metal ions"

PMID:18650437

A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis.

NFS1 forms complex with ISD11

"A variant of Nfs1 was purified in conjunction with Isd11 in a heterologous expression system in Escherichia coli"

PMID:21298097

Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.

ISD11 is part of preformed ISCU/NFS1/ISD11 complex

"frataxin interacts with a preformed ISCU/NFS1/ISD11 complex rather than with the individual components to form a stable quaternary complex"

PMID:23593335

The L-cysteine desulfurase NFS1 is localized in the cytosol where it provides the sulfur for molybdenum cofactor biosynthesis in humans.

NFS1 and ISD11 localize to mitochondria and nucleus

"NFS1 and ISD11 are present in mitochondria and in the nucleus"
ISD11 is a stabilization factor for NFS1

"ISD11 was described as a stabilization factor of NFS1 which is essential for its activity in FeS cluster formation in mitochondria"

PMID:26342079

Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19.

PMID:27499296

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PMID:27519411

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.

PMID:28634302

Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.

Crystal structure shows ISD11 subunits form dimeric core of SDA complex

"the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex"
ACP acyl chain occupies hydrophobic core of ISD11

"the 4'-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization"
ISD11 clarifies critical role in eukaryotic Fe-S assemblies

"a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies"

PMID:29097656

Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex.

Crystal structures of NFS1-ISD11-ACP complexes with/without ISCU

"we present crystal structures of three different NFS1-ISD11-ACP complexes with and without ISCU"
ISD11 homodimerizes in the complex

"Crystal structures of (NFS1-ISD11-ACP)2 and (NFS1-ISD11-ACP-ISCU)2 complexes"

PMID:31101807

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.

3.2A cryo-EM structure of NFS1-ISD11-ACP-ISCU-FXN complex

"Here the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer"
ISD11 is accessory protein in core ISC complex

"cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP"

PMID:31664822

Structure of the Human ACP-ISD11 Heterodimer.

2.0A crystal structure of ACP-ISD11 heterodimer

"the structure of the human mitochondrial ACP-ISD11 heterodimer was determined at 2.0 Å resolution"
Phosphopantetheine-acyl chain interacts with ISD11 residues

"The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11"
ACP-ISD11 modulates NFS1 foldability

"modulating together with ACP the foldability of ISD11"

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:34824239

N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization.

High resolution crystal structures of NFS1-ISD11-ACP-ISCU2 complexes

"we crystallized the dimeric (NIAU2)2 complex containing wild-type or various mutant ISCU2 proteins...for wild-type ISCU2, diffracted up to 1.8 Å resolution"

Reactome:R-HSA-1362408

FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster

Reactome:R-HSA-1362416

Frataxin binds iron

Reactome:R-HSA-9854984

Transfer of Fe-S clusters to SDHB

Reactome:R-HSA-9866272

2Fe-2S is inserted in UQCRFS1

file:human/LYRM4/LYRM4-deep-research-falcon.md

Deep research report on LYRM4

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(LYRM4-deep-research-falcon.md)

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organism: human
gene_id: LYRM4
gene_symbol: LYRM4
uniprot_accession: Q9HD34
protein_description: 'RecName: Full=LYR motif-containing protein 4 {ECO:0000305};'
gene_info: Name=LYRM4 {ECO:0000312|HGNC:HGNC:21365}; Synonyms=C6orf149, ISD11; ORFNames=CGI-203;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the complex I LYR family. .
protein_domains: Complex1_LYR_dom. (IPR008011); Complex1_LYR_LYRM4. (IPR045297);
ISC_assembly_LYR. (IPR051522); Complex1_LYR (PF05347)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9HD34
Protein Description: RecName: Full=LYR motif-containing protein 4 {ECO:0000305};
Gene Information: Name=LYRM4 {ECO:0000312|HGNC:HGNC:21365}; Synonyms=C6orf149, ISD11; ORFNames=CGI-203;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the complex I LYR family. .
Key Domains: Complex1_LYR_dom. (IPR008011); Complex1_LYR_LYRM4. (IPR045297); ISC_assembly_LYR. (IPR051522); Complex1_LYR (PF05347)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "LYRM4" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'LYRM4' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene LYRM4 (gene ID: LYRM4, UniProt: Q9HD34) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9HD34
Protein Description: RecName: Full=LYR motif-containing protein 4 {ECO:0000305};
Gene Information: Name=LYRM4 {ECO:0000312|HGNC:HGNC:21365}; Synonyms=C6orf149, ISD11; ORFNames=CGI-203;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the complex I LYR family. .
Key Domains: Complex1_LYR_dom. (IPR008011); Complex1_LYR_LYRM4. (IPR045297); ISC_assembly_LYR. (IPR051522); Complex1_LYR (PF05347)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "LYRM4" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene LYRM4 (gene ID: LYRM4, UniProt: Q9HD34) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Human LYRM4 (ISD11; UniProt Q9HD34)

Identity verification and definitions
- Gene/protein identity and aliases: LYRM4 encodes a small LYR motif-containing protein also known as ISD11 in humans. It is a member of the mitochondrial LYRM superfamily and functions in the iron–sulfur (Fe–S) cluster (ISC) assembly machinery. Recent authoritative sources explicitly describe LYRM4 as ISD11 and place it in the mammalian ISC core complex (NFS1–LYRM4–ACP–ISCU) (maio2024ciao1lossof pages 1-2, zhong2023bola3andnfu1 pages 1-2).
- Organism: Homo sapiens, mitochondrial protein (maio2024ciao1lossof pages 1-2, zhong2023bola3andnfu1 pages 1-2).
- Family/domains: LYRM4 is part of the LYR motif-containing protein family that features an N‑terminal LYR motif and a conserved central triplet of α-helices; LYRM4 (Isd11) is among the most conserved family members and belongs to the Complex1_LYR domain-containing group (inferred by family-wide structural descriptions) (dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129, dohnalek2025evolucemitochondriálníbiogeneze. pages 130-131).

Key concepts and current mechanistic understanding
- Primary role in ISC biogenesis: LYRM4/ISD11 is a non-catalytic, essential accessory subunit of the cysteine desulfurase NFS1. In the de novo ISC pathway, a [2Fe–2S] cluster is assembled on the ISCU scaffold by a multiprotein complex comprising NFS1/LYRM4/ACP (NDUFAB1) with frataxin (FXN) and the ferredoxin/reductase pair (FDX2/FDXR) supplying electrons; HSC20/HSPA9 chaperones then mediate transfer to client carriers such as GLRX5/BOLA3 or to [4Fe–4S] assembly factors (ISCA1/ISCA2/NFU1) (zhong2023bola3andnfu1 pages 2-3, zhong2023bola3andnfu1 pages 1-2, maio2024ciao1lossof pages 1-2). Functionally, LYRM4 stabilizes and enables NFS1 catalytic activity and efficient 2Fe–2S synthesis on ISCU (solaveraUnknownyearfunctionalcharacterizationof pages 38-40, maio2024ciao1lossof pages 1-2).
- Complex composition and interactions: The early ISC complex in mammals is best represented as NFS1–LYRM4–mitochondrial acyl carrier protein (mtACP; NDUFAB1)–ISCU, with frataxin as an allosteric effector and electron input via FDX2/FDXR. This composition and the stepwise flow to GLRX5/BOLA3 and NFU1 nodes are supported by recent experimental studies (zhong2023bola3andnfu1 pages 2-3, zhong2023bola3andnfu1 pages 1-2, maio2024ciao1lossof pages 1-2).
- Subcellular localization: The mammalian ISC machinery, including NFS1 and LYRM4, operates in the mitochondrial matrix. Parallel ISC components can be detected in the cytosol/nucleus for downstream CIA-dependent maturation, but LYRM4/ISD11’s core role is mitochondrial (maio2024ciao1lossof pages 1-2). Older isolated reports of extra-mitochondrial LYRM localization have not been substantiated by recent evidence (dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24).

Recent developments and latest research (priority to 2023–2024)
- Pathway integration and updated ISC wiring: A 2023 study on mitoribosome Fe–S cluster assembly provided an updated, experimentally grounded map of mitochondrial Fe–S biogenesis and delivery, explicitly describing the de novo ISC complex as NFS1/LYRM4/ACP working with ISCU and frataxin, and quantifying dependencies of mitoribosome subunits on specific delivery nodes (GLRX5–BOLA3 and ISCA1–NFU1) (Nucleic Acids Research, Oct 12, 2023; https://doi.org/10.1093/nar/gkad842) (zhong2023bola3andnfu1 pages 1-2, zhong2023bola3andnfu1 pages 2-3).
- Human genetics of Fe–S pathways: A 2024 JCI study defined biallelic loss of CIAO1 as a new human disease and, in its mechanistic framework, summarized the mammalian ISC core complex—NFS1 with binding partner LYRM4 (ISD11), mtACP/NDUFAB1, ISCU, and FXN—underscoring the canonical role of LYRM4 in mitochondrial ISC (J Clin Invest, Jun 17, 2024; https://doi.org/10.1172/JCI179559) (maio2024ciao1lossof pages 1-2, maio2024ciao1lossof pages 2-4). Although this work focuses on the cytosolic CIA pathway, it affirms current consensus regarding LYRM4’s place in mitochondrial ISC.
- Structural insights: Family-wide structural analyses and literature synthesis (2025 review) consolidate that LYRM4 contains a conserved α-helical core forming a hydrophobic tunnel that accommodates the acyl chain of mtACP. This structural arrangement explains the frequently observed heterodimerization of LYRMs with acylated ACP and supports allosteric regulation of LYRM clients by mtACP’s acylation state. The review also collates prior subcomplex structures, including an ACP–ISD11 heterodimer and a human cysteine desulfurase subcomplex with defined acyl‑ACP–ISD11 contacts; comprehensive 2023–2024 cryo‑EM of the full NFS1–LYRM4–ACP–ISCU holocomplex remains represented by subcomplex data and predictive models (dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133, dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129). In parallel, 2023 mitoribosome cryo‑EM work pinpointed Fe–S sites in mitochondrial ribosomes, reinforcing the biological reach of ISC outputs (zhong2023bola3andnfu1 pages 1-2).

Current applications and real-world implementations
- Diagnostic frameworks: Modern diagnostic evaluation of suspected mitochondrial disorders increasingly incorporates the ISC pathway map placing LYRM4/ISD11 in the core de novo synthesis complex. Silencing experiments in human cells link depletion of ISC factors to impaired mitoribosome stability and mitochondrial protein synthesis, which can inform interpretation of patient fibroblast phenotypes and guide targeted testing of ISC/CIA genes (zhong2023bola3andnfu1 pages 1-2). The JCI 2024 work demonstrates how defining upstream ISC components (including LYRM4 in the NFS1–ISCU complex) helps interpret disorders of downstream CIA maturation and muscle-biopsy phenotypes, suggesting utility for integrated gene panels spanning ISC and CIA modules (maio2024ciao1lossof pages 1-2, maio2024ciao1lossof pages 2-4).
- Pathway-level therapeutic considerations: Although LYRM4 itself has no direct therapy, pathway knowledge connects mtACP acylation and mtFAS status to ISC function. This suggests that perturbations in mitochondrial fatty acid synthesis (mtFAS) or mtACP phosphopantetheinylation could secondarily impair NFS1–LYRM4 function and Fe–S assembly, informing research strategies in metabolic or neurodegenerative conditions where mtFAS or phosphopantetheinylation is disrupted (dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133, dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129).

Expert opinions and analysis (authoritative sources)
- The 2023 NAR study provides an experimental, system-level perspective that integrates de novo ISC assembly (NFS1/LYRM4/ACP/ISCU/FXN) with delivery nodes (GLRX5–BOLA3; ISCA1–NFU1) and outputs to mitoribosome function, effectively establishing a contemporary reference wiring for mammalian ISC that places LYRM4 centrally as NFS1’s binding partner (zhong2023bola3andnfu1 pages 1-2, zhong2023bola3andnfu1 pages 2-3).
- The 2024 JCI investigation frames LYRM4 within a consensus model for mammalian ISC and emphasizes the coexistence of ISC components in the mitochondrial matrix and in cytosol/nucleus (for CIA-dependent maturation), reinforcing the need to interpret phenotypes in light of compartmentalized Fe–S biogenesis (maio2024ciao1lossof pages 1-2).
- A 2025 synthesis of LYRM family biology argues that LYRM4 is the most conserved LYRM and likely ancestral, with a key regulatory axis through acylated mtACP that couples mitochondrial fatty acid metabolism to ISC activity, respiratory chain complex assembly, and mitoribosome function (dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 130-131). While mechanistic details remain under active study, the LYR motif and a conserved downstream phenylalanine (LYR‑F) emerge as critical for ACP engagement and functional output (dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129).

Relevant statistics and data (recent studies)
- Mitoribosome dependency on ISC nodes: In human cell models, silencing of ISC biosynthesis/delivery factors reduced mitoribosome stability and mitochondrial translation; the study mapped that mitoribosomal [2Fe–2S] clusters are supplied via the GLRX5–BOLA3 node and [4Fe–4S] into METTL17 via ISCA1–NFU1 (NAR 2023; specific quantitative readouts include sucrose-gradient fractionation and pulse labeling assays in HEK293T cells and patient fibroblasts) (zhong2023bola3andnfu1 pages 1-2, zhong2023bola3andnfu1 pages 3-4, zhong2023bola3andnfu1 pages 2-3).
- CIAO1 disease cohort (for broader Fe–S context): Four unrelated patients carried biallelic CIAO1 variants presenting with proximal/axial weakness, elevated CK, respiratory insufficiency, and deep-brain iron deposition; lentiviral restoration of CIAO1 rescued cellular defects in patient-derived cells, demonstrating causality (JCI 2024; published June 17, 2024) (maio2024ciao1lossof pages 2-4). While not a LYRM4 variant cohort, the study situates LYRM4 in the canonical upstream ISC complex that supports CIA-dependent Fe–S enzyme maturation (maio2024ciao1lossof pages 1-2).

Regulatory features and cross-pathway coupling
- LYR motif and ACP acylation: The LYR motif and adjacent conserved residues mediate binding of acidic mtACP, whose acyl chain inserts into a hydrophobic tunnel in LYRM4’s helical core. The acylation state of mtACP (NDUFAB1) likely acts as an allosteric regulator of LYRM4–NFS1 function, coupling mitochondrial fatty acid synthesis to Fe–S assembly and respiratory/mitoribosomal biogenesis (dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129, dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 130-131).
- Interaction dependencies: Experimentally validated and model-supported contacts between LYRM4, NFS1, and mtACP align with prior subcomplex structures (ACP–ISD11 and cysteine desulfurase assemblies), indicating that LYRM4 helps organize the early ISC complex and stabilize NFS1 for cysteine desulfurase activity (dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128, dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133).

Human disease associations
- Direct LYRM4 genetic disease evidence remains sparse in 2023–2024 primary reports retrieved here; however, curated resources and prior literature associate LYRM4 with combined oxidative phosphorylation deficiency phenotypes (e.g., COXPD19), and multiple recent studies frame LYRM4 mechanistically upstream of established Fe–S disease genes (e.g., NFU1, BOLA3, GLRX5) (zhong2023bola3andnfu1 pages 1-2, maio2024ciao1lossof pages 1-2). Given its essential role in ISC assembly with NFS1, LYRM4 dysfunction is expected to cause global defects in mitochondrial and CIA-dependent Fe–S client maturation, predicting combined OXPHOS deficiency and multisystem phenotypes similar to other ISC defects (zhong2023bola3andnfu1 pages 1-2, maio2024ciao1lossof pages 1-2).

Pathway placement and cellular localization summary
- LYRM4 operates in the mitochondrial matrix as the NFS1 binding partner in the de novo ISC complex, with ISCU as scaffold, mtACP/NDUFAB1 as an obligate partner, and FXN/FDX2/FDXR providing allosteric activation and electrons. Output flows through HSC20/HSPA9 to GLRX5/BOLA3 and ISCA1/ISCA2/NFU1 for distribution to 2Fe–2S and 4Fe–4S clients in mitochondria and further to CIA for nucleocytoplasmic enzymes (zhong2023bola3andnfu1 pages 2-3, zhong2023bola3andnfu1 pages 1-2, maio2024ciao1lossof pages 1-2).

Embedded evidence summary table
| Aspect | Evidence summary (1–2 sentences) | Key partners | Sources (journal, year, DOI/URL) |
|---|---|---|---|
| Identity / Aliases | Human LYRM4 (alias ISD11) is a small LYR-motif protein annotated as UniProt Q9HD34 and identified as the eukaryote-specific ISD11 subunit of the mitochondrial ISC machinery. | LYRM4 (ISD11) | NAR 2023 (Zhong et al.) https://doi.org/10.1093/nar/gkad842 (zhong2023bola3andnfu1 pages 1-2), Dohnálek 2025 review (dohnalek2025evolucemitochondriálníbiogeneze. pages 131-132) |
| Cellular localization | Predominantly mitochondrial (matrix/inner-membrane-associated ISC machinery); some older reports of extra-mitochondrial localization lack recent confirmation. | Mitochondrial ISC components | J Clin Invest 2024 (Maio et al.) https://doi.org/10.1172/JCI179559 (maio2024ciao1lossof pages 1-2), NAR 2023 (zhong2023bola3andnfu1 pages 1-2) |
| Molecular function | Non-catalytic accessory/stabilizing subunit that enables NFS1 cysteine desulfurase activity and efficient de novo 2Fe-2S cluster synthesis on ISCU; required for complex stability and cluster transfer. | NFS1, ISCU, frataxin, FDX2, HSC20/HSPA9 | J Clin Invest 2024 (maio2024ciao1lossof pages 1-2), Dohnálek 2025 (dohnalek2025evolucemitochondriálníbiogeneze. pages 131-132), Solavera excerpt (solaveraUnknownyearfunctionalcharacterizationof pages 38-40) |
| Complex composition | Core assembly includes NFS1–LYRM4–ACP (NDUFAB1)–ISCU scaffold, with HSC20/HSPA9 cochaperone system mediating cluster transfer and downstream carriers (GLRX5, NFU1, BOLA3, ISCA1/2). | NFS1, LYRM4, NDUFAB1 (mtACP), ISCU, HSC20, HSPA9, GLRX5, NFU1, BOLA3 | NAR 2023 (zhong2023bola3andnfu1 pages 1-2), J Clin Invest 2024 (maio2024ciao1lossof pages 1-2), Dohnálek 2025 (dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133) |
| Structural insights (2023–2024) | Experimental structures include an ACP–ISD11 heterodimer and structural descriptions of the Fe-S synthesis subcomplex; broader cryo-EM work (e.g., mitoribosome Fe-S sites) was reported in 2023, while full high-resolution cryo-EM of the complete NFS1–LYRM4–ACP–ISCU holocomplex remains represented by subcomplex structures and predictive models (AlphaFold-backed). | ACP (structural contact), NFS1, ISCU | PNAS/biochemistry structural citations summarized in Dohnálek 2025 (dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133), NAR 2023 (mitoribosome cryo-EM) (zhong2023bola3andnfu1 pages 1-2) |
| Regulatory features (LYR motif, ACP acylation) | The N-terminal LYR motif and adjacent conserved residues (LYR-F) mediate binding to acidic mtACP; acylation state of mtACP (NDUFAB1) alters LYRM4 function, linking metabolic state (mtFAS) to ISC activity. | LYR motif (LYRM4), NDUFAB1 (mtACP), acyl chain | Dohnálek 2025 (computational + literature synthesis) (dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129), NAR 2023 (zhong2023bola3andnfu1 pages 1-2) |
| Disease associations (2023–2024 context) | Perturbation of ISC/CIA pathways causes mitochondrial disorders; LYRM4 is implicated by association with combined OXPHOS deficiency phenotypes in databases and by mechanistic links to NFS1-dependent disease; direct LYRM4 human variant reports are limited but related ISC/CIA gene defects (e.g., NFU1, BOLA3, CIAO1) produce severe mitochondrial syndromes. | LYRM4 (implicated), NFS1, NFU1, BOLA3, CIAO1 | Open literature and genetic studies summarized in Maio 2024 JCI (maio2024ciao1lossof pages 1-2), NAR 2023 (zhong2023bola3andnfu1 pages 1-2), Dohnálek 2025 (dohnalek2025evolucemitochondriálníbiogeneze. pages 131-132) |
| Links to mtFAS via NDUFAB1 | LYRM4 forms a heterodimer with mitochondrial ACP (NDUFAB1); acylation of ACP (product of mtFAS) is proposed to allosterically regulate LYRM4-mediated activation of NFS1 and coordination of Fe-S assembly with respiratory complex biogenesis. | NDUFAB1 (mtACP), mtFAS enzymes, LYRM4 | Dohnálek 2025 (dohnalek2025evolucemitochondriálníbiogeneze. pages 129-130, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129), NAR 2023 (zhong2023bola3andnfu1 pages 1-2) |

Table: Compact evidence table summarizing identity, localization, molecular role, complex composition, structural/regulatory features, disease context, and mtFAS links for human LYRM4 (ISD11), with 2023–2024 prioritized sources (context IDs indicate the extracted evidence).

References with URLs and publication dates (where available)
- Zhong et al. 2023. BOLA3 and NFU1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Research. Advance access Oct 12, 2023. DOI: 10.1093/nar/gkad842. URL: https://doi.org/10.1093/nar/gkad842 (zhong2023bola3andnfu1 pages 1-2, zhong2023bola3andnfu1 pages 3-4, zhong2023bola3andnfu1 pages 2-3).
- Maio et al. 2024. CIAO1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic Fe–S enzymes. The Journal of Clinical Investigation. Published Jun 17, 2024. DOI: 10.1172/JCI179559. URL: https://doi.org/10.1172/JCI179559 (maio2024ciao1lossof pages 1-2, maio2024ciao1lossof pages 2-4).
- Dohnálek 2025. Evoluce mitochondriální biogeneze. Review synthesizing LYRM family structure-function, LYRM4–ACP interactions, and evolutionary context; cites ACP–ISD11 structural work and human Fe–S assembly subcomplex architecture (dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24, dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128, dohnalek2025evolucemitochondriálníbiogeneze. pages 131-132, dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129, dohnalek2025evolucemitochondriálníbiogeneze. pages 130-131).
- Solavera (thesis/excerpt; undated). Notes on NFS1 dimer with ISCU monomers and cooperation with ISD11 (LYRM4) and ACP; outlines canonical ISC steps and delivery factors (solaveraUnknownyearfunctionalcharacterizationof pages 38-40).

Notes and limitations
- Direct 2023–2024 primary reports of LYRM4 patient variants were not identified in the retrieved corpus; disease links for LYRM4 therefore rely on mechanistic placement, prior literature, and curated associations, whereas 2023–2024 patient-level statistics derive from related ISC/CIA genes (maio2024ciao1lossof pages 1-2). Future incorporation of newly published LYRM4 variant reports would refine genotype–phenotype correlations.

References

(maio2024ciao1lossof pages 1-2): Nunziata Maio, Rotem Orbach, Irina T. Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, A. Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey A. Rouault, and Carsten G. Bönnemann. Ciao1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic fe-s enzymes. The Journal of Clinical Investigation, Jun 2024. URL: https://doi.org/10.1172/jci179559, doi:10.1172/jci179559. This article has 13 citations.
(zhong2023bola3andnfu1 pages 1-2): Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, and Antoni Barrientos. Bola3 and nfu1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Research, 51:11797-11812, Oct 2023. URL: https://doi.org/10.1093/nar/gkad842, doi:10.1093/nar/gkad842. This article has 31 citations and is from a highest quality peer-reviewed journal.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 20-24): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 128-129): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 130-131): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(zhong2023bola3andnfu1 pages 2-3): Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, and Antoni Barrientos. Bola3 and nfu1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Research, 51:11797-11812, Oct 2023. URL: https://doi.org/10.1093/nar/gkad842, doi:10.1093/nar/gkad842. This article has 31 citations and is from a highest quality peer-reviewed journal.
(solaveraUnknownyearfunctionalcharacterizationof pages 38-40): D Jové Solavera. Functional characterization of novel mutations in x-linked sideroblastic anaemia (xlsa) and the identification of transferrin receptor as a causative gene for a …. Unknown journal, Unknown year.
(maio2024ciao1lossof pages 2-4): Nunziata Maio, Rotem Orbach, Irina T. Zaharieva, Ana Töpf, Sandra Donkervoort, Pinki Munot, Juliane Mueller, Tracey Willis, Sumit Verma, Stojan Peric, Deepa Krishnakumar, Sniya Sudhakar, A. Reghan Foley, Sarah Silverstein, Ganka Douglas, Lynn Pais, Stephanie DiTroia, Christopher Grunseich, Ying Hu, Caroline Sewry, Anna Sarkozy, Volker Straub, Francesco Muntoni, Tracey A. Rouault, and Carsten G. Bönnemann. Ciao1 loss of function causes a neuromuscular disorder with compromise of nucleocytoplasmic fe-s enzymes. The Journal of Clinical Investigation, Jun 2024. URL: https://doi.org/10.1172/jci179559, doi:10.1172/jci179559. This article has 13 citations.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 132-133): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 127-128): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(zhong2023bola3andnfu1 pages 3-4): Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A Shoubridge, and Antoni Barrientos. Bola3 and nfu1 link mitoribosome iron–sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome. Nucleic Acids Research, 51:11797-11812, Oct 2023. URL: https://doi.org/10.1093/nar/gkad842, doi:10.1093/nar/gkad842. This article has 31 citations and is from a highest quality peer-reviewed journal.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 131-132): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.
(dohnalek2025evolucemitochondriálníbiogeneze. pages 129-130): V Dohnálek. Evoluce mitochondriální biogeneze. Unknown journal, 2025.

Citations

2Fe–2S
4Fe–4S
https://doi.org/10.1093/nar/gkad842
https://doi.org/10.1172/JCI179559
https://doi.org/10.1172/jci179559,
https://doi.org/10.1093/nar/gkad842,

📄 View Raw YAML

id: Q9HD34
gene_symbol: LYRM4
aliases:
  - ISD11
  - C6orf149
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: Immunofluorescence analysis demonstrated that ISD11 
            co-localized with both frataxin and with mitochondria.
        - reference_id: PMID:23593335
          supporting_text: NFS1 and ISD11 are present in mitochondria and in the
            nucleus
        - reference_id: file:human/LYRM4/LYRM4-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: 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
  - term:
      id: GO:0005198
      label: structural molecule activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:28634302
          supporting_text: 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
  - term:
      id: GO:1990221
      label: L-cysteine desulfurase complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      reason: This is the correct cellular component annotation for LYRM4's 
        participation in the cysteine desulfurase complex.
      supported_by:
        - reference_id: PMID:28634302
          supporting_text: 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)
        - reference_id: PMID:31664822
          supporting_text: Recombinant human ACP-ISD11 was able to interact with
            the NFS1 desulfurase, thus yielding an active enzyme
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Nuclear localization of LYRM4 has been experimentally 
        demonstrated along with NFS1 (PMID:23593335). This IEA annotation is 
        consistent with experimental findings.
      action: ACCEPT
      reason: The IEA annotation is supported by experimental evidence from 
        subcellular fractionation and fluorescence microscopy showing NFS1 and 
        ISD11 in the nucleus.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1 and ISD11 are present in mitochondria and in the
            nucleus
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: This IEA annotation duplicates the IBA annotation for 
        mitochondrion. Both are correct and supported by strong experimental 
        evidence.
      action: ACCEPT
      reason: Mitochondrial localization is the primary site of LYRM4 function. 
        This IEA annotation is consistent with experimental evidence.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: Immunofluorescence analysis demonstrated that ISD11 
            co-localized with both frataxin and with mitochondria.
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: This IEA annotation from InterPro is consistent with the IBA 
        annotation and experimental evidence for LYRM4's role in iron-sulfur 
        cluster assembly.
      action: ACCEPT
      reason: The annotation is correct and well-supported by domain analysis 
        and experimental evidence.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: 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
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26342079
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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).
      supported_by:
        - reference_id: PMID:26342079
          supporting_text: '2015 Sep 4. Mapping Key Residues of ISD11 Critical for
            NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL
            DISORDER, COXPD19.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:27499296
    review:
      summary: Protein binding annotation from mitochondrial protein interaction
        mapping study. Too generic to be informative.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:27499296
          supporting_text: 2016 Aug 4. Mitochondrial Protein Interaction Mapping
            Identifies Regulators of Respiratory Chain Function.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding annotation from interactome study. 
        Uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too generic. More specific MF annotations exist
        for LYRM4.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal 
            cell-specific remodeling of the human interactome.
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: ACCEPT
      reason: This is accurate. LYRM4 is part of the core ISC assembly complex 
        that synthesizes [2Fe-2S] clusters on ISCU.
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: 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.
  - term:
      id: GO:0016604
      label: nuclear body
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1 and ISD11 are present in mitochondria and in the
            nucleus
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: NAS
    original_reference_id: PMID:27519411
    review:
      summary: NAS annotation for mitochondrial localization from the Complex 
        Portal paper on mitochondrial ISC assembly machinery architecture.
      action: ACCEPT
      reason: Mitochondrial localization is well-established for LYRM4.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: Immunofluorescence analysis demonstrated that ISD11 
            co-localized with both frataxin and with mitochondria.
        - reference_id: PMID:27519411
          supporting_text: Epub 2016 Aug 12. Architecture of the Human 
            Mitochondrial Iron-Sulfur Cluster Assembly Machinery.
  - term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    evidence_type: NAS
    original_reference_id: PMID:29097656
    review:
      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.
      action: ACCEPT
      reason: Iron-sulfur cluster assembly is the core biological process for 
        LYRM4.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: 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
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:28634302
    review:
      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.
      action: ACCEPT
      reason: Molecular adaptor activity accurately describes LYRM4's role in 
        bridging NFS1 and ACP within the cysteine desulfurase complex.
      supported_by:
        - reference_id: PMID:28634302
          supporting_text: The structure also reveals the 
            4'-phosphopantetheine-conjugated acyl-group of ACP occupies the 
            hydrophobic core of ISD11, explaining the basis of ACP 
            stabilization.
        - reference_id: PMID:31664822
          supporting_text: 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.
  - term:
      id: GO:0005198
      label: structural molecule activity
    evidence_type: IDA
    original_reference_id: PMID:28634302
    review:
      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).
      action: ACCEPT
      reason: Structural molecule activity is appropriate for LYRM4's role in 
        stabilizing NFS1 within the ISC complex.
      supported_by:
        - reference_id: PMID:28634302
          supporting_text: a pair of ISD11 subunits form the dimeric core of the
            SDA complex, which clarifies the critical role of ISD11 in 
            eukaryotic assemblies
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HTP
    original_reference_id: PMID:34800366
    review:
      summary: HTP annotation from quantitative mitochondrial proteome study. 
        Consistent with established mitochondrial localization.
      action: ACCEPT
      reason: Mitochondrial localization is the primary site of LYRM4 function.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: Immunofluorescence analysis demonstrated that ISD11 
            co-localized with both frataxin and with mitochondria.
        - reference_id: PMID:34800366
          supporting_text: Epub 2021 Nov 19. Quantitative high-confidence human 
            mitochondrial proteome and its dynamics in cellular context.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: IDA annotation for nuclear localization from subcellular 
        fractionation and microscopy study.
      action: ACCEPT
      reason: Nuclear localization has been demonstrated experimentally, though 
        the mitochondrial function is the primary role.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1 and ISD11 are present in mitochondria and in the
            nucleus
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:23593335
    review:
      summary: IDA annotation for mitochondrial localization from subcellular 
        fractionation and microscopy study.
      action: ACCEPT
      reason: Mitochondrial localization is well-established by this and 
        multiple other studies.
      supported_by:
        - reference_id: PMID:23593335
          supporting_text: NFS1 and ISD11 are present in mitochondria and in the
            nucleus
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31664822
    review:
      summary: This annotation captures LYRM4 interaction with NDUFAB1 (ACP) 
        from the ACP-ISD11 heterodimer structure paper. However, protein binding
        is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too generic. The interaction with ACP is better
        captured by the molecular adaptor activity and structural molecule 
        activity annotations.
      supported_by:
        - reference_id: PMID:31664822
          supporting_text: Epub 2019 Nov 8. Structure of the Human ACP-ISD11 
            Heterodimer.
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:31664822
    review:
      summary: LYRM4 participates in [2Fe-2S] cluster assembly as part of the 
        ACP-ISD11 heterodimer that stabilizes NFS1 and enables cluster synthesis
        on ISCU.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:31664822
          supporting_text: the NFS1/ACP-ISD11 core complex was activated by 
            frataxin and ISCU proteins
  - term:
      id: GO:0044572
      label: '[4Fe-4S] cluster assembly'
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: The core machinery for de novo biosynthesis of 
            iron-sulfur clusters (ISC), located in the mitochondria matrix, is a
            five-protein complex
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18650437
    review:
      summary: This annotation captures LYRM4 interaction with NFS1 from a study
        on NFS1 role in molybdenum cofactor biosynthesis. Protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too generic. The NFS1 interaction is better 
        captured by molecular adaptor activity and structural molecule activity 
        annotations.
      supported_by:
        - reference_id: PMID:18650437
          supporting_text: '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.'
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IDA
    original_reference_id: PMID:17331979
    review:
      summary: IDA annotation for mitochondrial localization from the 
        foundational study on ISD11 interaction with frataxin and NFS1/ISCU 
        complex.
      action: ACCEPT
      reason: This is strong experimental evidence for mitochondrial 
        localization from the paper that first characterized ISD11 function in 
        mammals.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: Immunofluorescence analysis demonstrated that ISD11 
            co-localized with both frataxin and with mitochondria.
  - term:
      id: GO:0044571
      label: '[2Fe-2S] cluster assembly'
    evidence_type: IDA
    original_reference_id: PMID:17331979
    review:
      summary: IDA annotation for [2Fe-2S] cluster assembly based on siRNA 
        knockdown experiments showing that ISD11 depletion leads to decreased 
        aconitase activity.
      action: ACCEPT
      reason: This is appropriate experimental evidence for LYRM4's role in Fe-S
        cluster assembly.
      supported_by:
        - reference_id: PMID:17331979
          supporting_text: 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
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:31101807
    review:
      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.
      action: ACCEPT
      reason: Structural evidence directly demonstrates LYRM4 is a component of 
        the mitochondrial [2Fe-2S] assembly complex.
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: 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.
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:29097656
    review:
      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).
      action: ACCEPT
      reason: Homodimerization of LYRM4/ISD11 is structurally demonstrated and 
        functionally relevant for complex assembly.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: Crystal structures of (NFS1-ISD11-ACP)2 and 
            (NFS1-ISD11-ACP-ISCU)2 complexes
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IDA
    original_reference_id: PMID:34824239
    review:
      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.
      action: ACCEPT
      reason: The crystal structures confirm LYRM4 homodimerization within the 
        ISC complex.
      supported_by:
        - reference_id: PMID:34824239
          supporting_text: we crystallized the dimeric (NIAU2)2 complex...NFS1 
            subunits are depicted in orange and yellow, ISD11 in purple and 
            magenta
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:29097656
    review:
      summary: Protein binding annotation from the structural study. Captures 
        interaction with NFS1 and ISCU. However, protein binding is 
        uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Protein binding is too generic. The specific interactions are 
        better captured by molecular adaptor activity and homodimerization 
        activity annotations.
      supported_by:
        - reference_id: PMID:29097656
          supporting_text: Structure and functional dynamics of the 
            mitochondrial Fe/S cluster synthesis complex.
  - term:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
    evidence_type: IDA
    original_reference_id: PMID:21298097
    review:
      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.
      action: ACCEPT
      reason: This study provides direct evidence that LYRM4/ISD11 is a 
        component of the Fe-S cluster assembly complex.
      supported_by:
        - reference_id: PMID:21298097
          supporting_text: 'Mammalian frataxin: an essential function for cellular
            viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur
            assembly complex'
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1362408
    review:
      summary: TAS annotation from Reactome pathway for [2Fe-2S] cluster 
        assembly. The ISC machinery operates in the mitochondrial matrix.
      action: ACCEPT
      reason: Mitochondrial matrix is the correct sub-compartment localization 
        for LYRM4 function in the ISC assembly machinery.
      supported_by:
        - reference_id: PMID:31101807
          supporting_text: The core machinery for de novo biosynthesis of 
            iron-sulfur clusters (ISC), located in the mitochondria matrix
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1362416
    review:
      summary: TAS annotation from Reactome pathway for frataxin binding iron. 
        Consistent with mitochondrial matrix localization of the ISC complex.
      action: ACCEPT
      reason: Mitochondrial matrix localization is correct for LYRM4.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9854984
    review:
      summary: TAS annotation from Reactome pathway for Fe-S cluster transfer to
        SDHB.
      action: ACCEPT
      reason: Mitochondrial matrix localization is correct for LYRM4.
  - term:
      id: GO:0005759
      label: mitochondrial matrix
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9866272
    review:
      summary: TAS annotation from Reactome pathway for [2Fe-2S] insertion into 
        UQCRFS1.
      action: ACCEPT
      reason: Mitochondrial matrix localization is correct for LYRM4.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data 
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation 
      data to orthologs using Ensembl Compara
    findings: []
  - id: PMID:17331979
    title: Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex 
      and multiple mitochondrial chaperones.
    findings:
      - statement: ISD11 co-localizes with frataxin and mitochondria
        supporting_text: Immunofluorescence analysis demonstrated that ISD11 
          co-localized with both frataxin and with mitochondria.
      - statement: ISD11 depletion causes decline of NFS1/ISCU complex and 
          aconitase activity
        supporting_text: 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
      - statement: Frataxin-ISD11 interaction is nickel-dependent
        supporting_text: The frataxin/ISD11 interaction was also decreased by 
          the chelator EDTA, and was increased by supplementation with nickel 
          but not other metal ions
  - id: PMID:18650437
    title: 'A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor
      for MOCS3, a protein involved in molybdenum cofactor biosynthesis.'
    findings:
      - statement: NFS1 forms complex with ISD11
        supporting_text: A variant of Nfs1 was purified in conjunction with 
          Isd11 in a heterologous expression system in Escherichia coli
  - id: PMID:21298097
    title: 'Mammalian frataxin: an essential function for cellular viability through
      an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex.'
    findings:
      - statement: ISD11 is part of preformed ISCU/NFS1/ISD11 complex
        supporting_text: frataxin interacts with a preformed ISCU/NFS1/ISD11 
          complex rather than with the individual components to form a stable 
          quaternary complex
  - id: PMID:23593335
    title: The L-cysteine desulfurase NFS1 is localized in the cytosol where it 
      provides the sulfur for molybdenum cofactor biosynthesis in humans.
    findings:
      - statement: NFS1 and ISD11 localize to mitochondria and nucleus
        supporting_text: NFS1 and ISD11 are present in mitochondria and in the 
          nucleus
      - statement: ISD11 is a stabilization factor for NFS1
        supporting_text: ISD11 was described as a stabilization factor of NFS1 
          which is essential for its activity in FeS cluster formation in 
          mitochondria
  - id: PMID:26342079
    title: 'Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability:
      IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19.'
    findings: []
  - id: PMID:27499296
    title: Mitochondrial Protein Interaction Mapping Identifies Regulators of 
      Respiratory Chain Function.
    findings: []
  - id: PMID:27519411
    title: Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly 
      Machinery.
    findings: []
  - id: PMID:28634302
    title: Structure of human Fe-S assembly subcomplex reveals unexpected 
      cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.
    findings:
      - statement: Crystal structure shows ISD11 subunits form dimeric core of 
          SDA complex
        supporting_text: the SDA structure adopts an unexpected architecture in 
          which a pair of ISD11 subunits form the dimeric core of the SDA 
          complex
      - statement: ACP acyl chain occupies hydrophobic core of ISD11
        supporting_text: the 4'-phosphopantetheine-conjugated acyl-group of ACP 
          occupies the hydrophobic core of ISD11, explaining the basis of ACP 
          stabilization
      - statement: ISD11 clarifies critical role in eukaryotic Fe-S assemblies
        supporting_text: a pair of ISD11 subunits form the dimeric core of the 
          SDA complex, which clarifies the critical role of ISD11 in eukaryotic 
          assemblies
  - id: PMID:29097656
    title: Structure and functional dynamics of the mitochondrial Fe/S cluster 
      synthesis complex.
    findings:
      - statement: Crystal structures of NFS1-ISD11-ACP complexes with/without 
          ISCU
        supporting_text: we present crystal structures of three different 
          NFS1-ISD11-ACP complexes with and without ISCU
      - statement: ISD11 homodimerizes in the complex
        supporting_text: Crystal structures of (NFS1-ISD11-ACP)2 and 
          (NFS1-ISD11-ACP-ISCU)2 complexes
  - id: PMID:31101807
    title: Structure of the human frataxin-bound iron-sulfur cluster assembly 
      complex provides insight into its activation mechanism.
    findings:
      - statement: 3.2A cryo-EM structure of NFS1-ISD11-ACP-ISCU-FXN complex
        supporting_text: "Here the 3.2 Å resolution cryo-electron microscopy structure
          of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN
          hetero-pentamer"
      - statement: ISD11 is accessory protein in core ISC complex
        supporting_text: cysteine desulfurase NFS1 that is activated by frataxin
          (FXN), scaffold protein ISCU, accessory protein ISD11, and 
          acyl-carrier protein ACP
  - id: PMID:31664822
    title: Structure of the Human ACP-ISD11 Heterodimer.
    findings:
      - statement: 2.0A crystal structure of ACP-ISD11 heterodimer
        supporting_text: "the structure of the human mitochondrial ACP-ISD11 heterodimer
          was determined at 2.0 Å resolution"
      - statement: Phosphopantetheine-acyl chain interacts with ISD11 residues
        supporting_text: The 4'-phosphopantetheine-acyl chain, which is 
          covalently bound to ACP, interacts with several residues of ISD11
      - statement: ACP-ISD11 modulates NFS1 foldability
        supporting_text: modulating together with ACP the foldability of ISD11
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the 
      human interactome.
    findings: []
  - id: PMID:34800366
    title: Quantitative high-confidence human mitochondrial proteome and its 
      dynamics in cellular context.
    findings: []
  - id: PMID:34824239
    title: N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by 
      ISCU2 dimerization.
    findings:
      - statement: High resolution crystal structures of NFS1-ISD11-ACP-ISCU2 
          complexes
        supporting_text: "we crystallized the dimeric (NIAU2)2 complex containing
          wild-type or various mutant ISCU2 proteins...for wild-type ISCU2, diffracted
          up to 1.8 Å resolution"
  - id: Reactome:R-HSA-1362408
    title: FXN:NFS1:ISD11:ISCU assembles 2Fe-2S iron-sulfur cluster
    findings: []
  - id: Reactome:R-HSA-1362416
    title: Frataxin binds iron
    findings: []
  - id: Reactome:R-HSA-9854984
    title: Transfer of Fe-S clusters to SDHB
    findings: []
  - id: Reactome:R-HSA-9866272
    title: 2Fe-2S is inserted in UQCRFS1
    findings: []
  - id: file:human/LYRM4/LYRM4-deep-research-falcon.md
    title: Deep research report on LYRM4
    findings: []
core_functions:
  - description: LYRM4/ISD11 is an essential non-catalytic subunit that provides
      structural stabilization for NFS1 cysteine desulfurase. Crystal structures
      show that ISD11 subunits form the dimeric core of the cysteine desulfurase
      complex (PMID:28634302). ISD11 depletion leads to decline of the NFS1/ISCU
      complex (PMID:17331979).
    molecular_function:
      id: GO:0005198
      label: structural molecule activity
    directly_involved_in:
      - id: GO:0044571
        label: '[2Fe-2S] cluster assembly'
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:1990221
      label: L-cysteine desulfurase complex
  - description: LYRM4 functions as a molecular adaptor bridging NFS1 and 
      acyl-ACP (NDUFAB1). The hydrophobic core of ISD11 accommodates the 
      phosphopantetheine-acyl chain of ACP, linking mitochondrial fatty acid 
      synthesis to Fe-S cluster biogenesis (PMID:28634302, PMID:31664822).
    molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    directly_involved_in:
      - id: GO:0016226
        label: iron-sulfur cluster assembly
    locations:
      - id: GO:0005759
        label: mitochondrial matrix
    in_complex:
      id: GO:0099128
      label: mitochondrial [2Fe-2S] assembly complex
proposed_new_terms: []
suggested_questions:
  - question: Is LYRM4 required for NFS1 function in the nucleus/cytosol, or 
      only in mitochondria?
  - question: What is the functional significance of nuclear LYRM4 localization?
  - question: How does the acylation state of NDUFAB1/ACP regulate LYRM4-NFS1 
      complex activity?
suggested_experiments:
  - description: Conditional knockout of LYRM4 in different cellular 
      compartments to assess compartment-specific functions
  - description: Mass spectrometry analysis of LYRM4 interactome in nuclear vs 
      mitochondrial fractions
  - description: Structure determination of cytosolic NFS1-LYRM4 complex if it 
      exists
tags:
  - iron-sulfur-cluster-biogenesis

LYRM4

Gene Description

Existing Annotations Review

Core Functions

LYRM4 functions as a molecular adaptor bridging NFS1 and acyl-ACP (NDUFAB1). The hydrophobic core of ISD11 accommodates the phosphopantetheine-acyl chain of ACP, linking mitochondrial fatty acid synthesis to Fe-S cluster biogenesis (PMID:28634302, PMID:31664822).

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