title: Oligomerization propensity and flexibility of yeast frataxin studied by X-ray crystallography and small-angle X-ray scattering.
abstract: Frataxin is a mitochondrial protein with a central role in iron homeostasis. Defects in frataxin function lead to Friedreich's ataxia, a progressive neurodegenerative disease with childhood onset. The function of frataxin has been shown to be closely associated with its ability to form oligomeric species; however, the factors controlling oligomerization and the types of oligomers present in solution are a matter of debate. Using small-angle X-ray scattering, we found that Co(2+), glycerol, and a single amino acid substitution at the N-terminus, Y73A, facilitate oligomerization of yeast frataxin, resulting in a dynamic equilibrium between monomers, dimers, trimers, hexamers, and higher-order oligomers. Using X-ray crystallography, we found that Co(2+) binds inside the channel at the 3-fold axis of the trimer, which suggests that the metal has an oligomer-stabilizing role. The results reveal the types of oligomers present in solution and support our earlier suggestions that the trimer is the main building block of yeast frataxin oligomers. They also indicate that different mechanisms may control oligomer stability and oligomerization in vivo.
authors: Center for Molecular Protein Science, Institute for Chemistry and Chemical Engineering, Lund University, SE-221 00 Lund, Sweden.
authors: Christopher A G
authors: CA
authors: Söderberg
authors: Alexander V
authors: AV
authors: Shkumatov
authors: Sreekanth
authors: S
authors: Rajan
authors: Oleksandr
authors: O
authors: Gakh
authors: Dmitri I
authors: DI
authors: Svergun
authors: Grazia
authors: G
authors: Isaya
authors: Salam
authors: S
authors: Al-Karadaghi
mesh_terms: D000595:Amino Acid Sequence; D003035:Cobalt / Q000737:chemistry; D018360:Crystallography, X-Ray; D005990:Glycerol / Q000737:chemistry; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D058105:Polymerization; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics; D053838:Scattering, Small Angle; D000096923:Frataxin
chemical_list: D003035:Cobalt; D005990:Glycerol; D033862:Iron-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin