module: dmel_iron_sulfur_cluster_assembly title: Mitochondrial and cytosolic iron-sulfur cluster assembly in Drosophila melanogaster label: Iron-sulfur cluster assembly module_type: BIOLOGICAL_PROCESS description: >- Iron-sulfur (Fe-S) clusters are cofactors of respiratory complexes, the TCA cycle, DNA replication and repair enzymes and many other proteins. In eukaryotes all clusters depend on the mitochondrial iron-sulfur cluster (ISC) machinery. In the matrix, the cysteine desulfurase Nfs1, stabilised by Isd11 (bcn92) and acyl-ND-ACP, supplies sulfur and frataxin (fh) stimulates assembly of a [2Fe-2S] cluster on the scaffold IscU, with electrons from ferredoxin (Fdx1) and ferredoxin reductase (dare). The Hsc20-Hsc70-5 chaperone pair with glutaredoxin 5 transfers the cluster to client proteins, and the ISA proteins (MagR, CG13623) with IBA57 (CG8043) convert [2Fe-2S] into [4Fe-4S] clusters for mitochondrial targets. A sulfur-containing compound made by the ISC machinery is exported by the ABC transporter Abcb7 and used by the cytosolic iron-sulfur protein assembly (CIA) system: the diflavin reductase CG13667 and anamorsin (Ciapin1) supply electrons, the Nubp1-Nubp2 scaffold builds [4Fe-4S] clusters, and the CIA targeting complex (Ciao1, CG17683, galla2 and Mms19) inserts them into cytosolic and nuclear apoproteins. summary: >- Mitochondrial ISC and cytosolic CIA machineries that build [2Fe-2S] and [4Fe-4S] clusters and deliver them to mitochondrial, cytosolic and nuclear proteins. concepts: - {id: GO:0016226, label: iron-sulfur cluster assembly} parts: - id: isc_core_complex label: Mitochondrial core ISC complex role: de novo [2Fe-2S] cluster synthesis on IscU module_type: PROTEIN_COMPLEX complex: true group: NIAUF complex_term: {id: GO:1990229, label: iron-sulfur cluster assembly complex} processes: - {id: GO:0044571, label: "[2Fe-2S] cluster assembly"} unit_functions: Nfs1: {id: GO:0031071, label: cysteine desulfurase activity} roles: Nfs1: cysteine desulfurase that supplies sulfur bcn92: Isd11 (LYRM4) stabiliser of Nfs1 ND-ACP: acyl carrier protein that binds Isd11 IscU: scaffold on which the [2Fe-2S] cluster is assembled fh: frataxin, allosteric activator of sulfur transfer - id: isc_electron_supply label: Mitochondrial ferredoxin electron supply role: electron supply for cluster synthesis module_type: MODULE genes: [Fdx1, dare] unit_functions: Fdx1: {id: GO:0009055, label: electron transfer activity} dare: {id: GO:0004324, label: ferredoxin-NADP+ reductase activity} - id: cluster_transfer label: Chaperone-mediated cluster transfer role: release of [2Fe-2S] clusters from IscU and transfer to recipients module_type: MODULE genes: [Hsc20, Hsc70-5, Grx5] roles: Hsc20: J-protein co-chaperone that binds IscU Hsc70-5: mitochondrial Hsp70 that releases the cluster from IscU Grx5: monothiol glutaredoxin that carries [2Fe-2S] clusters - id: mito_4fe4s_assembly label: Mitochondrial [4Fe-4S] cluster assembly role: conversion of [2Fe-2S] to [4Fe-4S] clusters for mitochondrial proteins module_type: MODULE processes: - {id: GO:0044572, label: "[4Fe-4S] cluster assembly"} parts: - id: isa_complex label: ISA complex role: ISCA1-ISCA2 A-type carrier pair module_type: PROTEIN_COMPLEX complex: true group: ISA processes: - {id: GO:0044572, label: "[4Fe-4S] cluster assembly"} - id: iba57 label: IBA57 role: partner of the ISA proteins in [4Fe-4S] assembly module_type: MODULE genes: [CG8043] processes: - {id: GO:0044572, label: "[4Fe-4S] cluster assembly"} - id: isc_export label: Export to the cytosol role: export of the ISC-derived sulfur compound module_type: TRANSPORT_STEP genes: [Abcb7] function: {id: GO:0140481, label: ABC-type iron-sulfur cluster transporter activity} - id: cia_electron_supply label: CIA electron supply role: NADPH-dependent electron supply to the CIA scaffold module_type: MODULE genes: [CG13667, Ciapin1] roles: CG13667: NDOR1 diflavin reductase Ciapin1: anamorsin, [2Fe-2S] protein that receives electrons from CG13667 - id: cia_scaffold label: CIA scaffold complex role: assembly of [4Fe-4S] clusters in the cytosol module_type: PROTEIN_COMPLEX complex: true group: CIA-SCAF processes: - {id: GO:0044572, label: "[4Fe-4S] cluster assembly"} - id: cia_targeting_complex label: CIA targeting complex role: insertion of [4Fe-4S] clusters into cytosolic and nuclear apoproteins module_type: PROTEIN_COMPLEX complex: true group: CTC complex_term: {id: GO:0097361, label: "cytosolic [4Fe-4S] assembly targeting complex"} roles: Ciao1: CIAO1 WD40 subunit CG17683: CIAO3 (NARFL) [4Fe-4S] protein that receives clusters from the scaffold galla2: CIAO2B (MIP18 family) subunit Mms19: MMS19 subunit that binds client apoproteins connections: - source: isc_electron_supply target: isc_core_complex connection_type: PROVIDES_INPUT_FOR description: Reduced Fdx1 provides electrons for [2Fe-2S] cluster synthesis. - source: isc_core_complex target: cluster_transfer connection_type: PRECEDES description: The cluster built on IscU is released by Hsc20-Hsc70-5 and passed to Grx5. - source: cluster_transfer target: mito_4fe4s_assembly connection_type: PRECEDES description: "[2Fe-2S] clusters are converted to [4Fe-4S] clusters by the ISA proteins and IBA57." - source: isc_core_complex target: isc_export connection_type: PRECEDES description: A sulfur compound made by the ISC machinery is exported by Abcb7. - source: isc_export target: cia_scaffold connection_type: PROVIDES_INPUT_FOR description: The exported compound is required for cluster assembly on the Nubp1-Nubp2 scaffold. - source: cia_electron_supply target: cia_scaffold connection_type: PROVIDES_INPUT_FOR description: CG13667 and anamorsin supply electrons for [4Fe-4S] assembly on the scaffold. - source: cia_scaffold target: cia_targeting_complex connection_type: PRECEDES description: The CIA targeting complex transfers scaffold-built clusters to apoproteins. notes: >- Boundary. The module joins five FlyBase groups: the general Fe-S cluster assembly group (FESCA) and the four complex groups NIAUF (core ISC complex), ISA, CIA-SCAF and CTC. Every FESCA member is placed in one step. Fly subunit roles follow orthology to the human and yeast ISC and CIA proteins (for example bcn92 = Isd11/LYRM4, CG8043 = IBA57, CG13667 = NDOR1, CG17683 = CIAO3/NARFL, galla2 = CIAO2B); most have not been studied directly in flies. Molecular functions are given only to Nfs1, Fdx1, dare and Abcb7, whose activities are well conserved; the scaffold and carrier proteins have no clean catalytic activity. ND-ACP is also part of mitochondrial fatty acid synthesis (dmel_mitochondrial_fatty_acid_synthesis) and of respiratory complex I. The exact sulfur-containing compound exported by Abcb7 is not known. MagR has also been proposed as a magnetoreceptor; that proposal is not modelled. knowledge_gaps: - gap_statement: >- The chemical identity of the sulfur-containing compound that Abcb7 exports from mitochondria for cytosolic Fe-S cluster assembly is not known. boundary: Mitochondrial export step linking ISC and CIA machineries. gap_kind: [BIOLOGY]