Cytosolic iron-sulfur cluster assembly (Homo sapiens)

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4, 5, 9, 101, 3, 76, 82NUBP24Fe-4SNUBP1 NARFLCIAO1FAM96BMMS19 NDOR1CIAPIN1 oxidized mitochondrial matrixNDOR1CIAPIN1 reduced CIAPIN14Fe-4S2Fe-2S oxidized ABC7 dimer mitochondrionNARFL4Fe-4S NDOR1FADFMN NDOR1FADFMN NUBP14Fe-4S cytosolNUBP14Fe-4S CIAPIN14Fe-4S2Fe-2S reduced NUBP14Fe-4SCIAPIN1 NDOR1CIAPIN1 reduced4Fe-4S cluster NDOR1 4Fe-4S cluster 4Fe-4S cluster FAD FMN NUBP1 NADP+NADPHSNDOR1 NUBP2NARFLFeHoloprotein Containing 4Fe-4S ClusterFAD NUBP1 ABC7 dimerNUBP2 FAM96B CIAO1 NDOR1CIAPIN1 oxidized4Fe-4S cluster FMN NUBP24Fe-4SNUBP14Fe-4S cluster MMS19ABCB7H+Apoprotein Lacking 4Fe-4S ClusterNARFLCIAO1FAM96BMMS19CIAPIN1


Description

Iron-sulfur clusters containing 4 atoms of iron and 4 atoms of sulfur (4Fe-4S clusters) are assembled in the cytosol on a heterotetrameric scaffold composed of NUBP2 and NUBP1 subunits (reviewed in Lill et al. 2012, Rouault et al. 2012, Sharma et al. 2010, Lill and Mühlenhoff 2006). The sources of iron and sulfur are uncertain but the process requires a sulfur-containing compound exported from mitochondria via ABCB7 (ABC7). Newly synthesized 4Fe-4S are transferred to apoproteins such as XPD and POLD1 via the CIA targeting complex, composed of NARFL, CIAO1, FAM96B, and MMS19. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=2564830

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Bibliography

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  1. Stehling O, Netz DJ, Niggemeyer B, Rösser R, Eisenstein RS, Puccio H, Pierik AJ, Lill R.; ''Human Nbp35 is essential for both cytosolic iron-sulfur protein assembly and iron homeostasis.''; PubMed Europe PMC Scholia
  2. van Wietmarschen N, Moradian A, Morin GB, Lansdorp PM, Uringa EJ.; ''The mammalian proteins MMS19, MIP18, and ANT2 are involved in cytoplasmic iron-sulfur cluster protein assembly.''; PubMed Europe PMC Scholia
  3. Gari K, León Ortiz AM, Borel V, Flynn H, Skehel JM, Boulton SJ.; ''MMS19 links cytoplasmic iron-sulfur cluster assembly to DNA metabolism.''; PubMed Europe PMC Scholia
  4. Rouault TA.; ''Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease.''; PubMed Europe PMC Scholia
  5. Lill R, Mühlenhoff U.; ''Iron-sulfur protein biogenesis in eukaryotes: components and mechanisms.''; PubMed Europe PMC Scholia
  6. Lill R, Hoffmann B, Molik S, Pierik AJ, Rietzschel N, Stehling O, Uzarska MA, Webert H, Wilbrecht C, Mühlenhoff U.; ''The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism.''; PubMed Europe PMC Scholia
  7. Stehling O, Vashisht AA, Mascarenhas J, Jonsson ZO, Sharma T, Netz DJ, Pierik AJ, Wohlschlegel JA, Lill R.; ''MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity.''; PubMed Europe PMC Scholia
  8. Zhang Y, Lyver ER, Nakamaru-Ogiso E, Yoon H, Amutha B, Lee DW, Bi E, Ohnishi T, Daldal F, Pain D, Dancis A.; ''Dre2, a conserved eukaryotic Fe/S cluster protein, functions in cytosolic Fe/S protein biogenesis.''; PubMed Europe PMC Scholia
  9. Sharma AK, Pallesen LJ, Spang RJ, Walden WE.; ''Cytosolic iron-sulfur cluster assembly (CIA) system: factors, mechanism, and relevance to cellular iron regulation.''; PubMed Europe PMC Scholia
  10. Netz DJ, Stümpfig M, Doré C, Mühlenhoff U, Pierik AJ, Lill R.; ''Tah18 transfers electrons to Dre2 in cytosolic iron-sulfur protein biogenesis.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114954view16:47, 25 January 2021ReactomeTeamReactome version 75
113398view11:47, 2 November 2020ReactomeTeamReactome version 74
112602view15:57, 9 October 2020ReactomeTeamReactome version 73
101518view11:38, 1 November 2018ReactomeTeamreactome version 66
101054view21:20, 31 October 2018ReactomeTeamreactome version 65
100585view19:53, 31 October 2018ReactomeTeamreactome version 64
100134view16:39, 31 October 2018ReactomeTeamreactome version 63
99684view15:08, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93798view13:37, 16 August 2017ReactomeTeamreactome version 61
93335view11:20, 9 August 2017ReactomeTeamreactome version 61
87164view19:19, 18 July 2016MkutmonOntology Term : 'classic metabolic pathway' added !
86422view09:17, 11 July 2016ReactomeTeamreactome version 56
83191view10:19, 18 November 2015ReactomeTeamVersion54
81752view09:52, 26 August 2015ReactomeTeamVersion53
76892view08:16, 17 July 2014ReactomeTeamFixed remaining interactions
76597view11:57, 16 July 2014ReactomeTeamFixed remaining interactions
75928view09:58, 11 June 2014ReactomeTeamRe-fixing comment source
75630view10:50, 10 June 2014ReactomeTeamReactome 48 Update
74985view13:50, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74629view08:41, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
4Fe-4S cluster MetaboliteCHEBI:49883 (ChEBI)
ABC7 dimerComplexREACT_111663 (Reactome)
ABCB7ProteinO75027 (Uniprot-TrEMBL)
Apoprotein Lacking 4Fe-4S ClusterProteinREACT_160775 (Reactome)
MetaboliteCHEBI:33737 (ChEBI)
MetaboliteCHEBI:33738 (ChEBI)
CIAO1 ProteinO76071 (Uniprot-TrEMBL)
CIAPIN1 ProteinQ6FI81 (Uniprot-TrEMBL)
FAD MetaboliteCHEBI:16238 (ChEBI)
FAM96B ProteinQ9Y3D0 (Uniprot-TrEMBL)
FMN MetaboliteCHEBI:17621 (ChEBI)
FeMetaboliteCHEBI:18248 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
Holoprotein Containing 4Fe-4S ClusterComplexREACT_161124 (Reactome)
MMS19ProteinQ96T76 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NARFL

CIAO1 FAM96B

MMS19		ComplexREACT_160698 (Reactome)
NARFLProteinQ9H6Q4 (Uniprot-TrEMBL)
NDOR1 CIAPIN1 oxidizedComplexREACT_160955 (Reactome)
NDOR1 CIAPIN1 reducedComplexREACT_161272 (Reactome)
NDOR1 ProteinQ9UHB4 (Uniprot-TrEMBL)
NUBP1 4Fe-4SComplexREACT_160544 (Reactome)
NUBP1 ProteinP53384 (Uniprot-TrEMBL)
NUBP2

4Fe-4S

NUBP1		ComplexREACT_161484 (Reactome)
NUBP2 ProteinQ9Y5Y2 (Uniprot-TrEMBL)
NUBP2ProteinQ9Y5Y2 (Uniprot-TrEMBL)
SMetaboliteCHEBI:26833 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ABC7 dimerREACT_160314 (Reactome)
Apoprotein Lacking 4Fe-4S ClusterREACT_160250 (Reactome)
FeREACT_160314 (Reactome)
H+ArrowREACT_160077 (Reactome)
Holoprotein Containing 4Fe-4S ClusterArrowREACT_160250 (Reactome)
NADP+ArrowREACT_160077 (Reactome)
NADPHREACT_160077 (Reactome)
NARFL

CIAO1 FAM96B

MMS19		ArrowREACT_160250 (Reactome)
NARFL

CIAO1 FAM96B

MMS19		REACT_160250 (Reactome)
NDOR1 CIAPIN1 oxidizedREACT_160077 (Reactome)
NDOR1 CIAPIN1 reducedArrowREACT_160077 (Reactome)
NDOR1 CIAPIN1 reducedREACT_160314 (Reactome)
NUBP1 4Fe-4SArrowREACT_160250 (Reactome)
NUBP1 4Fe-4SREACT_160314 (Reactome)
NUBP2

4Fe-4S

NUBP1		REACT_160250 (Reactome)
NUBP2ArrowREACT_160250 (Reactome)
NUBP2REACT_160314 (Reactome)
REACT_160077 (Reactome) Cytosolic Fe/S protein biogenesis depends on the electron transfer chain from NAD(P)H to the Fe/S protein (CIAPIN1 in humans, DRE2 in yeast) via the flavoprotein NDOR1 (TAH18 in yeast). The precise role of electrons in the assembly process is unclear but in the absence of the electron chain the stable [4Fe-4S] cluster of NUBP1 is not assembled. CIAPIN1 binds two Fe/S clusters of the [2Fe-2S] and the [4Fe-4S] type. The [2Fe-2S] cluster is reduced by NDOR1-NADPH.
REACT_160250 (Reactome) A complex of four proteins termed CIA targeting complex is involved in the delivery of the NUBP1-NUBP2-bound Fe/S cluster to specific target apoproteins. NARFL (IOP1, Nar1 in yeast) is similar in sequence to iron-only hydrogenases and binds two [4Fe-4S] clusters. These cofactors are essential for biogenesis but their molecular function is unknown. The WD40 domain protein CIAO1 (Cia1 in yeast) forms a propeller-like structure which may serve as a docking site for the other members of the CIA targeting complex. The role of FAM96B (YHR122W, CIA2 in yeast) and MMS19 is still unclear, but they show some specificity for the delivery of Fe/S clusters into certain target apoproteins. They directly interact with numerous Fe/S target proteins including many proteins involved in nuclear DNA integrity and maintenance such as DNA polymerases (POLD1), helicases of the DNA repair pathway (XPD or FANCJ) or of telomere maintenance (RTEL1), and primases. Cells with mutated MMS19 are hypersensitive to DNA damage and have elongated telomeres therefore these target proteins are relevant to various cancer-related diseases and aging.
REACT_160314 (Reactome) A [4Fe-4S] cluster is assembled on a scaffold composed of the P-loop NTPases NUBP2 (CFD1 in yeast) and NUBP1 (Nbp35 in yeast) in a nucleotide-dependent fashion. The two proteins form a heterotetramer which transiently binds the [4Fe-4S] cluster in a bridged form between two subunits of the complex. The Fe/S cluster is bound to two highly conserved Cys residues in the C-termini of each of these proteins. NUBP1 contains an additional, stably associated [4Fe-4S] cluster at its N-terminus which is essential for function.
Mitochondria play a crucial role in cytosolic and nuclear Fe/S protein biogenesis. They export via a mitochondrial ABC transporter (yeast ATM1, human ABCB7) a still unknown, sulfur-containing compound which is essential for Fe/S cluster assembly in the cytosol.
The general cytosolic iron donor, the multi-domain monothiol glutaredoxin (human GRX3 or PICOT, yeast Grx3-Grx4) plays a crucial role in cytosolic-nuclear Fe/S protein biogenesis. The precise molecular function of the glutaredoxin is still unclear.
SREACT_160314 (Reactome)
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