Gene Symbol: LYRM4
Description: LYR motif containing 4
Alias: C6orf149, CGI-203, COXPD19, ISD11, LYR motif-containing protein 4, homolog of yeast Isd11, mitochondrial matrix Nfs1 interacting protein
Species: human
Products:     LYRM4

Top Publications

  1. Majmudar J, Feng X, Fox N, Nabhan J, Towle T, Ma T, et al. 4'-Phosphopantetheine and long acyl chain-dependent interactions are integral to human mitochondrial acyl carrier protein function. Medchemcomm. 2019;10:209-220 pubmed publisher that ACPM interacts with endogenous Fe-S cluster complex components through binding of the LYRM protein ISD11/LYRM4. Using knockdown experiments, we further determine that ACPM is essential for the stability of mitochondrial ..
  2. Fox N, Martelli A, Nabhan J, JANZ J, Borkowska O, Bulawa C, et al. Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity. Biochimie. 2018;152:211-218 pubmed publisher
    Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN)...
  3. Webert H, Freibert S, Gallo A, Heidenreich T, Linne U, Amlacher S, et al. Functional reconstitution of mitochondrial Fe/S cluster synthesis on Isu1 reveals the involvement of ferredoxin. Nat Commun. 2014;5:5013 pubmed publisher
    ..of [2Fe-2S] clusters on the mitochondrial scaffold protein Isu1 requires the cysteine desulphurase complex Nfs1-Isd11, frataxin, ferredoxin Yah1 and its reductase Arh1...
  4. Cai K, Frederick R, Dashti H, Markley J. Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering. Structure. 2018;26:1127-1136.e4 pubmed publisher
    ..The human mitochondrial cysteine desulfurase complex consists of two copies each of NFS1, ISD11, and acyl carrier protein...
  5. Yoon H, Knight S, Pandey A, Pain J, Turkarslan S, Pain D, et al. Turning Saccharomyces cerevisiae into a Frataxin-Independent Organism. PLoS Genet. 2015;11:e1005135 pubmed publisher
    ..interacting with other components of the Fe-S cluster machinery, including cysteine desulfurase Nfs1, Isd11 and the Isu1 scaffold protein. Yeast Isu1 with the methionine to isoleucine substitution (M141I), in which the E...
  6. Fox N, Das D, Chakrabarti M, Lindahl P, Barondeau D. Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex. Biochemistry. 2015;54:3880-9 pubmed publisher
    ..In human mitochondria, a core Fe-S assembly complex [called SDUF and composed of NFS1, ISD11, ISCU2, and frataxin (FXN) proteins] synthesizes Fe-S clusters from iron, cysteine sulfur, and reducing ..
  7. Bar Yaacov D, Hadjivasiliou Z, Levin L, Barshad G, Zarivach R, Bouskila A, et al. Mitochondrial Involvement in Vertebrate Speciation? The Case of Mito-nuclear Genetic Divergence in Chameleons. Genome Biol Evol. 2015;7:3322-36 pubmed publisher
    ..Increased chameleon sample size (N = 70) confirmed the geographic differentiation in POLRMT, NDUFA5, ACO1, LYRM4, MARS2, and ACAD9. Structural and functionality evaluation of these NSSs revealed high functionality...
  8. Cai K, Frederick R, Tonelli M, Markley J. Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly. J Inorg Biochem. 2018;183:107-116 pubmed publisher
    ..the two proteins interact mutually when each is bound to the cysteine desulfurase complex ([NFS1]2:[ISD11]2:[Acp]2), abbreviated as (NIA)2, where "N" represents the cysteine desulfurase (..
  9. Fox N, Chakrabarti M, McCormick S, Lindahl P, Barondeau D. The Human Iron-Sulfur Assembly Complex Catalyzes the Synthesis of [2Fe-2S] Clusters on ISCU2 That Can Be Transferred to Acceptor Molecules. Biochemistry. 2015;54:3871-9 pubmed publisher
    ..In human mitochondria, the core Fe-S biosynthetic enzymatic complex (called SDUF) consists of NFS1, ISD11, ISCU2, and frataxin (FXN) protein components...

More Information


  1. Cory S, Van Vranken J, Brignole E, Patra S, Winge D, Drennan C, et al. Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. Proc Natl Acad Sci U S A. 2017;114:E5325-E5334 pubmed publisher
    ..biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP)...
  2. Rocha A, Knight S, Pandey A, Yoon H, Pain J, Pain D, et al. Cysteine desulfurase is regulated by phosphorylation of Nfs1 in yeast mitochondria. Mitochondrion. 2018;40:29-41 pubmed publisher
    The cysteine desulfurase Nfs1/Isd11 uses the amino acid cysteine as the substrate and its activity is absolutely required for contributing persulfide sulfur to the essential process of iron-sulfur (Fe-S) cluster assembly in mitochondria...
  3. Anderson C, Massey D, Barrett J, Prescott N, Tremelling M, Fisher S, et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology. 2009;136:523-9.e3 pubmed publisher
    ..Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD...
  4. Jablensky A, Angelicheva D, Donohoe G, Cruickshank M, Azmanov D, Morris D, et al. Promoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia. Mol Psychiatry. 2012;17:1328-39 pubmed publisher
    ..The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins...
  5. Lai C, Chiu J, Lin W. Identification of the human crooked neck gene by comparative gene identification. Biochim Biophys Acta. 2001;1517:449-54 pubmed
    ..The unique features of the 16 copies of the tetratrico peptide repeat (TPR) motif were conserved in the yeast, fly and human crooked neck orthologous proteins, which were important for spliceosome assembly in cells. ..
  6. Weersma R, Stokkers P, Cleynen I, Wolfkamp S, Henckaerts L, Schreiber S, et al. Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort. Am J Gastroenterol. 2009;104:630-8 pubmed publisher
    ..We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions. ..
  7. Friemel M, Marelja Z, Li K, Leimkuhler S. The N-Terminus of Iron-Sulfur Cluster Assembly Factor ISD11 Is Crucial for Subcellular Targeting and Interaction with l-Cysteine Desulfurase NFS1. Biochemistry. 2017;56:1797-1808 pubmed publisher
    ..In humans, the function of NFS1 depends on the ISD11 protein, which is required to stabilize its structure...
  8. Boniecki M, Freibert S, Muhlenhoff U, Lill R, Cygler M. Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex. Nat Commun. 2017;8:1287 pubmed publisher
    ..scaffold protein ISCU and requires cysteine desulfurase NFS1, ferredoxin, frataxin, and the small factors ISD11 and ACP (acyl carrier protein)...
  9. Saha P, Srivastava S, Kumar S K P, Sinha D, D Silva P. Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19. J Biol Chem. 2015;290:25876-90 pubmed publisher
    ..relevant ISD11 mutation (R68L) has been associated in the development of a mitochondrial genetic disorder, COXPD19. Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex ..
  10. Cai K, Tonelli M, Frederick R, Markley J. Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron-Sulfur Cluster Biosynthesis. Biochemistry. 2017;56:487-499 pubmed publisher
    ..protein complex responsible for cluster assembly, which contains cysteine desulfurase (NFS1), ISD11 (also known as LYRM4), and acyl carrier protein (Acp)...
  11. Cleynen I, Mahachie John J, Henckaerts L, Van Moerkercke W, Rutgeerts P, Van Steen K, et al. Molecular reclassification of Crohn's disease by cluster analysis of genetic variants. PLoS ONE. 2010;5:e12952 pubmed publisher
    ..The used technique can be applied to other common complex diseases as well, and will help to complete patient characterization, in order to evolve towards personalized medicine. ..
  12. Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007;16:929-41 pubmed
    ..Another interactor was ISD11, recently identified as a component of the eukaryotic complex Nfs1/ISCU, an essential component of iron-sulfur ..
  13. Greliche N, Germain M, Lambert J, Cohen W, Bertrand M, Dupuis A, et al. A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis. BMC Med Genet. 2013;14:36 pubmed publisher
    ..This study, the first genome-wide SNP interaction analysis conducted so far on VT risk, suggests that common SNPs are unlikely exerting strong interactive effects on the risk of disease. ..
  14. Gakh O, Ranatunga W, Smith D, Ahlgren E, Al Karadaghi S, Thompson J, et al. Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery. J Biol Chem. 2016;291:21296-21321 pubmed
    ..four proteins involved in the initial step of Fe-S cluster synthesis: FXN42-210 (iron donor); [NFS1]·[ISD11] (sulfur donor); and ISCU (scaffold upon which new clusters are assembled)...
  15. Gakh O, Ranatunga W, Galeano B, Smith D, Thompson J, Isaya G. Defining the Architecture of the Core Machinery for the Assembly of Fe-S Clusters in Human Mitochondria. Methods Enzymol. 2017;595:107-160 pubmed publisher a pyridoxal phosphate-dependent cysteine desulfurase (human NFS1) and its stabilizing-binding partner (human ISD11), and (ii) elemental iron, provided by an iron-binding protein of the frataxin family (human FXN)...
  16. Lim S, Friemel M, Marum J, Tucker E, Bruno D, Riley L, et al. Mutations in LYRM4, encoding iron-sulfur cluster biogenesis factor ISD11, cause deficiency of multiple respiratory chain complexes. Hum Mol Genet. 2013;22:4460-73 pubmed publisher
    ..Here, we report a homozygous mutation in LYRM4 in two patients with combined OXPHOS deficiency...
  17. Angerer H, Schönborn S, Gorka J, Bahr U, Karas M, Wittig I, et al. Acyl modification and binding of mitochondrial ACP to multiprotein complexes. Biochim Biophys Acta Mol Cell Res. 2017;1864:1913-1920 pubmed publisher the complex I bound fraction, ACPM1 is present as a free matrix protein and in complex with the soluble LYRM4(ISD11)/NFS1 complex implicated in Fe-S cluster biogenesis...
  18. Calvo S, Compton A, Hershman S, Lim S, Lieber D, Tucker E, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4:118ra10 pubmed publisher
    ..The pathogenicity of two such genes, NDUFB3 and AGK, was supported by complementation studies and evidence from multiple patients, respectively. The results underscore the potential and challenges of deploying NGS in clinical settings. ..
  19. Shi Y, Ghosh M, Tong W, Rouault T. Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis. Hum Mol Genet. 2009;18:3014-25 pubmed publisher
    ..of proteins of diverse functions that contain the conserved tripeptide 'LYR' near the N-terminus, and it includes Isd11, which was previously observed to have an important role in iron-sulfur (Fe-S) cluster biogenesis in Saccharomyces ..
  20. Adam A, Bornhovd C, Prokisch H, Neupert W, Hell K. The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria. EMBO J. 2006;25:174-83 pubmed
    ..essential protein of the mitochondrial matrix, which is highly conserved from yeast to human and which we termed Isd11. Depletion of Isd11 caused a strong reduction in the levels of the Fe/S proteins aconitase and the Rieske protein, ..
  21. Dzul S, Rocha A, Rawat S, Kandegedara A, Kusowski A, Pain J, et al. In vitro characterization of a novel Isu homologue from Drosophila melanogaster for de novo FeS-cluster formation. Metallomics. 2017;9:48-60 pubmed publisher
    ..assembly is provided by cysteine desulfurase "Nfs1", a protein that works in union with its accessory protein "Isd11"...
  22. Yan R, Friemel M, Aloisi C, Huynen M, Taylor I, Leimkuhler S, et al. The Eukaryotic-Specific ISD11 Is a Complex-Orphan Protein with Ability to Bind the Prokaryotic IscS. PLoS ONE. 2016;11:e0157895 pubmed publisher
    The eukaryotic protein Isd11 is a chaperone that binds and stabilizes the central component of the essential metabolic pathway responsible for formation of iron-sulfur clusters in mitochondria, the desulfurase Nfs1...