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Sökning: onr:"swepub:oai:lup.lub.lu.se:b738ce02-fa4a-4161-990c-b81ee37a85e7" > Architecture of the...

Architecture of the human mitochondrial iron-sulfur cluster assembly machinery

Ranatunga, Wasantha (författare)
Gakh, Oleksandr (författare)
Galeano, Belinda K (författare)
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Smith, Douglas Y (författare)
Söderberg, Christopher, (författare)
Lunds universitet, Lund University, MAX IV-laboratoriet, MAX IV Laboratory
Al-Karadaghi, Salam, (författare)
Lunds universitet, Lund University, Lunds Tekniska Högskola, Faculty of Engineering, LTH, Institutioner vid LTH, Departments at LTH, Kemiska institutionen, Department of Chemistry, Centrum för Molekylär Proteinvetenskap, Center for Molecular Protein Science, Biokemi och Strukturbiologi, Biochemistry and Structural Biology
Thompson, James R (författare)
Isaya, Grazia (författare)
Ahlgren, Eva Christina, (författare)
Lunds universitet, Lund University, Lunds Tekniska Högskola, Faculty of Engineering, LTH, Institutioner vid LTH, Departments at LTH, Kemiska institutionen, Department of Chemistry, Centrum för Molekylär Proteinvetenskap, Center for Molecular Protein Science
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2016
Engelska 26 s.
Ingår i: Journal of Biological Chemistry. - ASBMB. - 0021-9258. ; 291:40, s. 21296-21321
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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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.

Ämnesord

NATURVETENSKAP  -- Biologiska vetenskaper -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska grundvetenskaper -- Annan medicinsk grundvetenskap (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Other Basic Medicine (hsv//eng)

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