Structural highlights
Disease
NFS1_HUMAN Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency.
Function
NFS1_HUMAN Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron-sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor.[1]
Publication Abstract from PubMed
Fe-S clusters, essential cofactors needed for the activity of many different enzymes, are assembled by conserved protein machineries inside bacteria and mitochondria. As the architecture of the human machinery remains undefined, we co-expressed in E. coli 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). We purified a stable, active complex consisting of all four proteins with 1:1:1:1 stoichiometry. Using negative staining transmission EM and single particle analysis, we obtained a three-dimensional model of the complex with ~14 A resolution. Molecular dynamics flexible fitting of protein structures docked into the EM map of the model revealed a [FXN42-210]24-[NFS1]24-[ISD11]24-[ISCU]24, complex, consistent with the measured 1:1:1:1 stoichiometry of its four components. The complex structure fulfills distance constraints obtained from chemical cross-linking of the complex at multiple recurring interfaces, involving hydrogen bonds, salt bridges or hydrophobic interactions between conserved residues. The complex consists of a central, roughly cubic [FXN42-210]24-[ISCU]24 sub-complex with one symmetric ISCU trimer bound on top of one symmetric FXN42-210 trimer at each of its eight vertices. Binding of twelve [NFS1]2-[ISD11]2 sub-complexes to the surface results in a globular macromolecule with diameter of ~15 nm, and creates 24 Fe-S cluster assembly centers. The organization of each center recapitulates a previously proposed, conserved mechanism for sulfur donation from NFS1 to ISCU and reveals - for the first time - a path for iron donation from FXN42-210 to ISCU.
Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.,Gakh O, Ranatunga W, Smith DY 4th, Ahlgren EC, Al-Karadaghi S, Thompson JR, Isaya G J Biol Chem. 2016 Aug 12. pii: jbc.M116.738542. PMID:27519411[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Marelja Z, Stocklein W, Nimtz M, Leimkuhler S. A novel role for human Nfs1 in the cytoplasm: Nfs1 acts as a sulfur donor for MOCS3, a protein involved in molybdenum cofactor biosynthesis. J Biol Chem. 2008 Sep 12;283(37):25178-85. doi: 10.1074/jbc.M804064200. Epub 2008, Jul 23. PMID:18650437 doi:http://dx.doi.org/10.1074/jbc.M804064200
- ↑ Gakh O, Ranatunga W, Smith DY 4th, Ahlgren EC, Al-Karadaghi S, Thompson JR, Isaya G. Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery. J Biol Chem. 2016 Aug 12. pii: jbc.M116.738542. PMID:27519411 doi:http://dx.doi.org/10.1074/jbc.M116.738542
