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Showing LYRM4 — ISD11 is a alias.

LYRM4

LYR motif-containing protein 4 · UniProt Q9HD34

Length
91 aa
Mass
10.8 kDa
Annotated
2026-06-10
19 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LYRM4 (ISD11) is a small LYR-motif mitochondrial protein that functions as an essential eukaryotic component of the cysteine desulfurase machinery that initiates iron-sulfur (Fe/S) cluster biogenesis (PMID:16341090, PMID:16341089). It forms a stable complex with the cysteine desulfurase NFS1 (Nfs1/ISCS), stabilizing the desulfurase against aggregation and altering its oligomeric state, such that loss of ISD11 abrogates Fe/S cluster loading onto the Isu/ISCU scaffold (PMID:16341090, PMID:16341089, PMID:24045011). In the assembled NFS1-ISD11-ACP (SDA) complex, ISD11 subunits form the dimeric core of the eukaryotic enzyme, and the 4'-phosphopantetheine-acyl chain of acyl carrier protein (ACP) occupies the hydrophobic core of ISD11, an interaction required for ISD11 folding and stability; this architecture leaves an incompletely formed substrate channel and solvent-exposed PLP cofactor, accounting for frataxin's role as an allosteric activator in eukaryotes (PMID:28634302, PMID:28233492, PMID:31664822). The SDA complex assembles with ISCU and frataxin into a stable quaternary complex, and ISD11 residues including the N-terminal LYR motif and helix-3 Arg-68 are critical for NFS1 interaction, complex stability, and downstream Fe/S-dependent respiratory chain function (PMID:21298097, PMID:26342079, PMID:28271877). Through its control of Fe/S cluster assembly, ISD11 governs the activity of aconitases and the electron transport chain and influences cellular iron homeostasis via IRP regulation (PMID:17331979, PMID:19454487). A homozygous R68L missense mutation in human LYRM4 causes combined OXPHOS deficiency by destabilizing the ISD11-NFS1 complex and abolishing cysteine desulfurase activity (PMID:23814038, PMID:26342079).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 High

    Established that ISD11 is an indispensable, eukaryote-specific partner of the cysteine desulfurase NFS1/Nfs1 acting at the earliest step of Fe/S cluster biogenesis, answering whether a dedicated factor stabilizes the desulfurase.

    Evidence Genetic depletion in yeast with co-IP, enzymatic activity assays, iron incorporation, and Isu scaffold loading, replicated by two independent labs

    PMID:16341089 PMID:16341090

    Open questions at the time
    • Did not define the structural basis of NFS1 stabilization
    • Stoichiometry and full complex composition not resolved
  2. 2007 Medium

    Connected human ISD11 to frataxin and to disease, showing the desulfurase complex is a target of Friedreich's ataxia mutations and a regulator of cellular iron.

    Evidence Co-IP/mass spectrometry, siRNA knockdown, aconitase and iron content assays in mammalian cells

    PMID:17331979

    Open questions at the time
    • Whether frataxin binds ISD11 directly or via the core complex unresolved here
    • Single lab
  3. 2009 Medium

    Demonstrated that human ISD11 controls both mitochondrial and cytosolic Fe/S-dependent enzymes and iron-regulatory protein activity, linking it to whole-cell iron homeostasis.

    Evidence Subcellular fractionation, co-IP with NFS1/ISCS, RNAi, aconitase and IRP activity assays

    PMID:19454487

    Open questions at the time
    • Reported nuclear localization not mechanistically explained
    • Single lab
  4. 2011 Medium

    Showed frataxin engages a preformed ISCU/NFS1/ISD11 core rather than individual components, defining the quaternary complex frataxin acts upon.

    Evidence In vivo and in vitro co-IP with size-exclusion chromatography of a ~190 kDa complex

    PMID:21298097

    Open questions at the time
    • Did not resolve subunit arrangement or stoichiometry
    • ACP not yet identified as a subunit
  5. 2013 High

    Identified a disease-causing LYRM4 mutation (R68L) and established ISD11's effect on the oligomeric state of the desulfurase, tying a specific residue to enzyme function and OXPHOS.

    Evidence MitoExome/Sanger sequencing, yeast complementation, in vitro cysteine desulfurase assay with mutant; separate biophysical oligomeric-state analysis

    PMID:23814038 PMID:24045011

    Open questions at the time
    • Structural mechanism by which R68L destabilizes the complex not defined at this stage
  6. 2015 High

    Mapped the ISD11 surface required for NFS1 binding through systematic mutagenesis, defining residues whose loss causes NFS1 aggregation, ISCU depletion, and respiratory failure.

    Evidence Site-directed mutagenesis with co-IP, aggregation assays, ETC complex activity, respiration, and iron/ROS measurements

    PMID:26342079

    Open questions at the time
    • Lacked atomic structure to interpret residue contributions
    • ACP contribution not yet incorporated
  7. 2017 High

    Solved the architecture of the SDA complex, revealing ISD11 dimers as the core, ACP's acyl chain buried in ISD11, and the structural basis for frataxin acting as an allosteric activator.

    Evidence X-ray crystallography and cryo-EM with enzyme kinetics and cell-based complementation; recombinant co-expression with defined [ACP]2:[ISD11]2:[NFS1]2 stoichiometry and in vitro Fe/S assays; N-terminal LYR-motif mutagenesis

    PMID:28233492 PMID:28271877 PMID:28634302

    Open questions at the time
    • Dynamics of substrate channel formation during catalysis not captured
    • How acyl-chain identity tunes activity not resolved
  8. 2018 Medium

    Established ACP as a folding chaperone for ISD11 and confirmed the ACP-ISD11 module binds and modulates NFS1 activity, clarifying why ACP is required for complex stability.

    Evidence Recombinant co-expression, co-purification, structural characterization, and NFS1 activity assays

    PMID:29737835

    Open questions at the time
    • Single lab
    • Physiological acyl-chain occupancy in vivo not quantified
  9. 2019 High

    Provided a high-resolution ACP-ISD11 heterodimer structure detailing the interface and acyl-chain contacts that modulate ISD11 foldability and enable NFS1 activation by frataxin and ISCU.

    Evidence 2.0 Å X-ray crystallography, molecular dynamics, NFS1 activity and interaction assays

    PMID:31664822

    Open questions at the time
    • Conformational changes upon frataxin/ISCU binding not captured in this structure
    • Single lab
  10. 2010 Medium

    Extended ISD11 function beyond Fe/S clusters by showing it is required for cytoplasmic and mitochondrial tRNA thiolation in Trypanosoma brucei, placing it at a sulfur-transfer hub.

    Evidence RNAi depletion, subcellular localization, and tRNA thiolation assays in a divergent eukaryote

    PMID:20442400

    Open questions at the time
    • Direct role in human tRNA thiolation not demonstrated
    • Single lab, divergent organism
  11. 2025 Low

    Linked elevated LYRM4 to altered metabolism in hepatocellular carcinoma via enhanced SDH activity and fumarate accumulation.

    Evidence Functional genomics, SDH activity assay, and metabolite measurement in HCC cells

    PMID:40320061

    Open questions at the time
    • No direct biochemical reconstitution described
    • Mechanism connecting LYRM4 to SDH activity not established
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the SDA complex dynamically coordinates frataxin and ISCU recruitment, ferredoxin electron delivery, and sulfur channeling during catalytic Fe/S cluster turnover, and whether human ISD11 directly supports tRNA thiolation, remain open.
  • No catalytic-cycle structure of the full assembly
  • Human tRNA thiolation role untested
  • Regulation of LYRM4 expression in disease contexts unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4
Localization
GO:0005739 mitochondrion 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
FXNISCUNDUFAB1NFS1
Complex memberships
ISCU/NFS1/ISD11 core complexNFS1-ISD11-ACP (SDA) cysteine desulfurase complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Isd11 (LYRM4 ortholog in yeast) forms a stable complex with the cysteine desulfurase Nfs1; in the absence of Isd11, Nfs1 is prone to aggregation, and Fe/S cluster assembly on scaffold proteins is abrogated, placing Isd11 at an early step in Fe/S cluster biogenesis. Genetic depletion, co-immunoprecipitation, enzymatic activity assays (aconitase, succinate dehydrogenase), iron incorporation into Leu1, holoform formation of ferredoxin Yah1 The EMBO journal High 16341089 16341090
2005 Isd11 is required for formation of an Fe/S cluster on the Isu scaffold proteins and is an indispensable eukaryotic component of the mitochondrial ISC-assembly machinery. Genetic deletion/depletion in yeast, Fe/S cluster loading assay on Isu scaffold, co-immunoprecipitation with Nfs1 The EMBO journal High 16341089
2007 Human ISD11 interacts with frataxin in mammalian cells; Friedreich's ataxia point mutations I154F and W155R in frataxin reduce the frataxin-ISD11 interaction; ISD11 depletion by siRNA reduces the NFS1/ISCU complex levels and aconitase activity while increasing cellular iron content. Co-immunoprecipitation, mass spectrometry, siRNA knockdown, aconitase activity assay, immunofluorescence co-localization Human molecular genetics Medium 17331979
2009 Human ISD11 localizes to both mitochondria and nucleus; it forms a stable in vivo complex with human cysteine desulfurase ISCS (NFS1); ISD11 knockdown inactivates mitochondrial and cytosolic aconitases, activates IRP1 iron-responsive element-binding activity, increases IRP2 protein levels, and causes abnormal ferric iron accumulations, linking ISD11 to cellular iron homeostasis. Subcellular fractionation/immunofluorescence, co-immunoprecipitation, RNA interference, aconitase activity assay, IRP activity assay Human molecular genetics Medium 19454487
2011 Mammalian frataxin interacts with a preformed ISCU/NFS1/ISD11 core complex (not individual components) to form a stable quaternary complex of ~190 kDa; this interaction defines the essential function of frataxin in Fe-S cluster biosynthesis. Co-immunoprecipitation (in vivo and in vitro), heterologous expression system, size-exclusion chromatography PloS one Medium 21298097
2013 A homozygous missense mutation R68L in human LYRM4/ISD11 causes combined OXPHOS deficiency (complexes I, II, III) and impairs Fe/S protein assembly; mutant ISD11 only partially complements yeast ISD11 deletion, and co-expression of mutant ISD11 with NFS1 yields nearly absent l-cysteine desulfurase activity in vitro. MitoExome sequencing, Sanger sequencing, yeast complementation assay, in vitro cysteine desulfurase activity assay with mutant protein Human molecular genetics High 23814038
2015 Key ISD11 residues in helix 1 (Phe-40), helix 3 (Leu-63, Arg-68, Gln-69, Ile-72, Tyr-76), and C-terminal segment (Leu-81, Glu-84) are critical for interaction with NFS1; mutations at these sites reduce NFS1 stability, cause NFS1 aggregation, deplete ISCU levels, impair Fe/S cluster biosynthesis, reduce ETC complex activity, and diminish mitochondrial respiration. The disease mutation R68L/R68A reduces ISD11-NFS1 complex stability and causes mitochondrial iron accumulation and ROS elevation. Site-directed mutagenesis, co-immunoprecipitation, NFS1 aggregation assay, aconitase activity, ETC complex activity assays, mitochondrial respiration measurements, iron/ROS detection The Journal of biological chemistry High 26342079
2017 Crystal and EM structures of the human NFS1-ISD11-ACP (SDA) complex reveal that ISD11 subunits form the dimeric core of the complex (not NFS1 as in prokaryotes); the 4'-phosphopantetheine-conjugated acyl group of ACP occupies the hydrophobic core of ISD11, explaining ACP's role in stabilizing ISD11; the architecture creates an incompletely formed substrate channel and solvent-exposed PLP cofactor, explaining why FXN acts as an allosteric activator in eukaryotes. X-ray crystallography, cryo-EM, enzyme kinetic assays, cell-based complementation studies Proceedings of the National Academy of Sciences of the United States of America High 28634302
2017 When NFS1 and ISD11 are co-expressed in E. coli, the active preparation contains E. coli acyl carrier protein (ACP) in a stoichiometric [Acp]2:[ISD11]2:[NFS1]2 complex; E. coli ACP can substitute for human ACP in supporting Fe/S cluster assembly in vitro. Recombinant co-expression, mass spectrometry stoichiometry determination, in vitro Fe/S cluster assembly assay ACS chemical biology High 28233492
2017 The first 10 N-terminal amino acids of ISD11, including the conserved LYR motif, are indispensable for NFS1 activity and for forming a stable, active complex with NFS1; N-terminal truncations also disrupt mitochondrial targeting. In vitro purified protein interaction assays, NFS1 activity assays with N-terminal ISD11 mutants, cell-based subcellular localization studies Biochemistry Medium 28271877
2013 Isd11 has a profound effect on the oligomeric state of Nfs1: the presence of Isd11 alters the quaternary structure of the eukaryotic cysteine desulfurase complex. Biochemical characterization of oligomeric state (size-exclusion chromatography / biophysical analysis) with and without Isd11 Biochemical and biophysical research communications Medium 24045011
2016 Human ISD11 alone exists in solution as an equilibrium of monomeric, dimeric, and tetrameric species; recombinant ISD11 expressed in E. coli co-purifies with bacterial IscS (the prokaryotic NFS1 ortholog) in a weak but specific interaction, indicating conservation of the desulfurase-binding surface. Analytical ultracentrifugation/gel filtration, co-purification from E. coli, binding specificity analysis PloS one Medium 27427956
2018 Human mitochondrial ACP and ISD11 form a soluble, structured, and stable complex when co-expressed in E. coli; ACP plays a key role in ISD11 folding and stability in vitro; the ACP-ISD11 complex binds NFS1 and modulates its cysteine desulfurase activity. Recombinant co-expression, co-purification, NFS1 activity assay, structural characterization ACS chemical biology Medium 29737835
2019 Crystal structure of the human mitochondrial ACP-ISD11 heterodimer at 2.0 Å resolution reveals stabilization via ionic interactions, hydrogen bonds, and apolar contacts; the 4'-phosphopantetheine-acyl chain of ACP interacts with specific ISD11 residues, modulating ISD11 foldability; the ACP-ISD11 complex interacts with NFS1 yielding an active enzyme that is further activated by frataxin and ISCU. X-ray crystallography (2.0 Å), molecular dynamics simulations, NFS1 activity assay, protein-protein interaction assay Biochemistry High 31664822
2010 In Trypanosoma brucei, Isd11 localizes to the mitochondrion and is required not only for Fe/S cluster assembly but also for both cytoplasmic and mitochondrial tRNA thiolation, placing Isd11 at the center of sulfur transfer pathways that connect Fe/S metabolism and tRNA modification. RNA interference (genetic depletion), subcellular fractionation/localization, biochemical tRNA thiolation assay The Journal of biological chemistry Medium 20442400
2025 Elevated LYRM4 expression enhances the enzymatic activity of succinate dehydrogenase (SDH), promoting fumarate accumulation in hepatocellular carcinoma cells. Functional genomics (TUIFGA), SDH enzymatic activity assay, cellular metabolite measurement Archives of biochemistry and biophysics Low 40320061

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Mammalian frataxin: an essential function for cellular viability through an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly complex. PloS one 190 21298097
2005 The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria. The EMBO journal 190 16341090
2005 Essential role of Isd11 in mitochondrial iron-sulfur cluster synthesis on Isu scaffold proteins. The EMBO journal 183 16341089
2017 Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proceedings of the National Academy of Sciences of the United States of America 127 28634302
2007 Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Human molecular genetics 125 17331979
2009 Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis. Human molecular genetics 119 19454487
2013 Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Human molecular genetics 92 23814038
2006 Evolution of the Isd11-IscS complex reveals a single alpha-proteobacterial endosymbiosis for all eukaryotes. Molecular biology and evolution 58 16648156
2021 Exosomes Isolated From Bone Marrow Mesenchymal Stem Cells Exert a Protective Effect on Osteoarthritis via lncRNA LYRM4-AS1-GRPR-miR-6515-5p. Frontiers in cell and developmental biology 45 34124036
2017 Mitochondrial Cysteine Desulfurase and ISD11 Coexpressed in Escherichia coli Yield Complex Containing Acyl Carrier Protein. ACS chemical biology 32 28233492
2010 The Fe/S cluster assembly protein Isd11 is essential for tRNA thiolation in Trypanosoma brucei. The Journal of biological chemistry 29 20442400
2015 Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19. The Journal of biological chemistry 26 26342079
2018 Rescuing the Rescuer: On the Protein Complex between the Human Mitochondrial Acyl Carrier Protein and ISD11. ACS chemical biology 21 29737835
2017 The N-Terminus of Iron-Sulfur Cluster Assembly Factor ISD11 Is Crucial for Subcellular Targeting and Interaction with l-Cysteine Desulfurase NFS1. Biochemistry 18 28271877
2019 Structure of the Human ACP-ISD11 Heterodimer. Biochemistry 17 31664822
2013 The effect of the adaptor protein Isd11 on the quaternary structure of the eukaryotic cysteine desulphurase Nfs1. Biochemical and biophysical research communications 15 24045011
2019 Iron-sulfur cluster ISD11 deficiency (LYRM4 gene) presenting as cardiorespiratory arrest and 3-methylglutaconic aciduria. JIMD reports 10 31497476
2016 The Eukaryotic-Specific ISD11 Is a Complex-Orphan Protein with Ability to Bind the Prokaryotic IscS. PloS one 8 27427956
2025 Integrated functional genomics-identified LYRM4 promotes fumarate accumulation and hepatocellular carcinoma progression. Archives of biochemistry and biophysics 1 40320061

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