Architecture of the human mitochondrial iron-sulfur cluster assembly machinery

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Gakh, OleksandrMayo Clinic Minnesota (author)

Architecture of the human mitochondrial iron-sulfur cluster assembly machinery

Article/chapterEnglish2016

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2016
26 s.

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LIBRIS-ID:oai:lup.lub.lu.se:b738ce02-fa4a-4161-990c-b81ee37a85e7
https://lup.lub.lu.se/record/b738ce02-fa4a-4161-990c-b81ee37a85e7URI
https://doi.org/10.1074/jbc.M116.738542DOI

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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 Escherichia coli the following 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 Å 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 12 [NFS1]2·[ISD11]2 sub-complexes to the surface results in a globular macromolecule with a 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.

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Ranatunga, WasanthaMayo Clinic Minnesota (author)
Smith, Douglas Y.Mayo Clinic Minnesota (author)
Ahlgren, Eva ChristinaLund University,Lunds universitet,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)mbfy-eca (author)
Al-Karadaghi, SalamLund University,Lunds universitet,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)mbfys-sa (author)
Thompson, James R.Mayo Clinic Minnesota (author)
Isaya, GraziaMayo Clinic Minnesota (author)
Mayo Clinic MinnesotaCentrum för Molekylär Proteinvetenskap (creator_code:org_t)

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In:Journal of Biological Chemistry291:40, s. 21296-213210021-9258

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