id: PW:0002636
rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0002636
title: cytosolic iron-sulfur cluster protein assembly pathway
description: The small inorganic Fe-S cluster (ISC) cofactor acts as an electron carrier in redox and
  catalytic reactions, and as a sulfur donor and environmental sensor. The ISC proteins can be found in
  mitochondria, cytoplasm and nucleus and are involved in energy production, tRNA modification and features
  of protein translation, DNA metabolism and repair. The steps in the assembly of iron-sulfur (Fe-S) clusters
  (ISC) and delivery to Fe-S proteins are part of the mitochondrial ISC biogenesis and the connected cytosolic
  assembly (CIA) pathways; ISCs provide for the maturation of all Fe-S proteins. A subset of the mitochondrial
  ISC pathway, termed 'core' and the mitochondrial ISC transport are essential for the function of the
  CIA pathway. Details of the cytosolic pathway are described here. A species still to be characterized,
  referred to as 'X-S', is delivered to the cytosol by the mitochondrial export pathway that includes
  the Abcb7 transporter, glutathione and the FAD-dependent intermembrane Gver (known as Alr) sulfhydryl
  oxidase. An initial [4Fe-4S] cluster is assembled on a scaffold composed of two P-loop NTPases, Nubp1
  and 2, forming a heterotetramer. A loosely bound [4Fe-4S] is coordinated by a conserved motif at the
  C-terminus of Nubp1. A tightly bound [4Fe-4S] is coordinated by a ferredoxin-like motif at the N-terminus
  of Nubp1. As in the mitochondrial pathway, electrons need to be supplied and the CIA electron system
  is composed of Ndor1 diflavin protein and the Fe-S protein Ciapin1. The two proteins interact with each
  other. Based on EPR studies of the yeast counterpart, electrons from NADPH are transferred to the [2Fe-2S]
  of Ciapin1 via the FAD and FMN centers of Ndor1. Release of [4Fe-4S] from the Nubp complex is followed
  by its transfer and insertion into recipient proteins. It requires the presence of Narfl (known as IOP)
  for transfer and the CIA targeting complex composed of Ciao1 (known as Cia1), Fam96a and b (known as
  CIA2A and B, respectively) and Mms19 proteins for insertion. Particular combinations of targeting proteins
  deliver the cluster to specific cytosolic and nuclear recipient apoproteins. Fam96a (CIA2A), for instance,
  is dedicated to the insertion of [4Fe-4S] into the iron regulatory protein ACO1 (known as IRP1) and
  maturation of the aconitase holoprotein. The dual function ACO1 (IRP1), and IRP2, are involved in the
  post-transcriptional control of iron homeostasis. Many molecular aspects of the CIA pathway remain to
  be characterized. Debilitating inherited conditions are associated with defects in the proteins involved
  in Fe-S formation, primarily in components of the ISC and transport pathways. To check the ontology
  report for annotations, GViewer, and download, click here
diagram_image: https://rgd.mcw.edu/pathway/PW0002636/cytosolic%20iron-sulfur%20cluster%20protein%20assembly%20pathway/pwmap.png
pathway_studio_file: https://rgd.mcw.edu/pathway/PW0002636/cytosolic%20iron-sulfur%20cluster%20protein%20assembly%20pathway/cytosolic%20iron-sulfur%20cluster%20protein%20assembly%20pathway.gpp
diagram_pathway_links:
- id: PW:0002635
  label: mitochondrial iron-sulfur cluster protein biogenesis pathway
- id: PW:0002637
  label: mitochondrial iron-sulfur cluster export pathway
diagram_gene_links:
- id: RGD:1307285
  label: Ciao1
- id: RGD:1549737
  label: Ciapin1
- id: RGD:1307481
  label: Fam96a
- id: RGD:1585802
  label: Fam96b
- id: RGD:727890
  label: Mms19
- id: RGD:1305982
  label: Narfl
- id: RGD:1308479
  label: Ndor1
- id: RGD:1310514
  label: Nubp1
- id: RGD:1305113
  label: Nubp2
diagram_chemicals: []
diagram_edges:
- source: Ciapin1
  relation: associated_with
  target: Ndor1
- source: Ndor1
  relation: positively_affects
  target: Ciapin1
- source: Nubp1
  relation: associated_with
  target: Nubp2
- source: Nubp1
  relation: positively_affects
  target: cytosolic recipients
- source: Nubp2
  relation: positively_affects
  target: nuclear recipients
diagram_labels:
- CIA targeting complex
diagram_other_links:
- href: /wg/home/pathway2/molecular-pathways2/cytosolic-recipients
  label: cytosolic recipients
- href: /wg/home/pathway2/molecular-pathways2/nuclear-recipients
  label: nuclear recipients
references:
- id: RGD:11554188
  citation: 'Barupala DP, etal., Arch Biochem Biophys. 2016 Feb 15;592:60-75. doi: 10.1016/j.abb.2016.01.010.
    Epub 2016 Jan 16.'
- id: RGD:11554190
  citation: 'Maio N and Rouault TA, Biochim Biophys Acta. 2015 Jun;1853(6):1493-512. doi: 10.1016/j.bbamcr.2014.09.009.
    Epub 2014 Sep 19.'
- id: RGD:11554192
  citation: 'Paul VD and Lill R, Biochim Biophys Acta. 2015 Jun;1853(6):1528-39. doi: 10.1016/j.bbamcr.2014.12.018.
    Epub 2015 Jan 10.'
- id: RGD:11554197
  citation: 'Lill R, etal., Eur J Cell Biol. 2015 Jul-Sep;94(7-9):280-91. doi: 10.1016/j.ejcb.2015.05.002.
    Epub 2015 May 31.'
- id: RGD:11554198
  citation: 'Pain D and Dancis A, Curr Opin Genet Dev. 2016 Jun;38:45-51. doi: 10.1016/j.gde.2016.03.006.
    Epub 2016 Apr 7.'
- id: RGD:11554199
  citation: 'Lane DJ, etal., Biochim Biophys Acta. 2015 May;1853(5):1130-44. doi: 10.1016/j.bbamcr.2015.01.021.
    Epub 2015 Feb 4.'
- id: RGD:11554200
  citation: Gakh O, etal., J Biol Chem. 2016 Sep 30;291(40):21296-21321. Epub 2016 Aug 12.