Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase.
Frataxin is a mitochondrial protein deficient in Friedreich ataxia (FRDA) and which is associated with abnormal intramitochondrial iron handling. We identified the mitochondrial processing peptidase beta (MPPbeta) as a frataxin protein partner using the yeast two-hybrid assay. In in vitro assays, MPPbeta binds frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41-210) that is processed further to the mature form. In vitro and in vivo experiments suggest that two C-terminal missense mutations found in FRDA patients modulate interaction with MPPbeta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, INSERM, Université Louis Pasteur, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex-Strasbourg, France.
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H
Koutnikova
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Campuzano
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M
Koenig
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers / Q000235:genetics; D019281:Dimerization; D005621:Friedreich Ataxia / Q000201:enzymology* / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D033862:Iron-Binding Proteins; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin
D017931:DNA Primers; D033862:Iron-Binding Proteins; D008666:Metalloendopeptidases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011994:Recombinant Proteins; D000096122:Mitochondrial Processing Peptidase; D000096923:Frataxin