Biochemistry, Department of
Date of this Version
2000
Citation
The Journal of Biological Chemistry, Vol. 275, No. 52, Issue of December 29, pp. 41469–41475, 2000
Abstract
We showed previously that maturation of the human
frataxin precursor (p-fxn) involves two cleavages by the
mitochondrial processing peptidase (MPP). This observation
was not confirmed by another group, however,
who reported only one cleavage. Here, we demonstrate
conclusively that MPP cleaves p-fxn in two sequential
steps, yielding a 18,826-Da intermediate (i-fxn) and a
17,255-Da mature (m-fxn) form, the latter corresponding
to endogenous frataxin in human tissues. The two cleavages
occur between residues 41–42 and 55–56, and both
match the MPP consensus sequence RX ↓ (X/S). Recombinant
rat and yeast MPP catalyze the pài step 4 and 40
times faster, respectively, than the i à m step. In isolated
rat mitochondria, p-fxn undergoes a sequence of
cleavages, p à i à m à d1 à d2, with d1 and d2 representing
two C-terminal fragments of m-fxn produced by
an unknown protease. The iàm step is limiting, and the
overall rate of p à i à m does not exceed the rate of mà
d1 à d2, such that the levels of m-fxn do not change
during incubations as long as 3 h. Inhibition of the iàm
step by a disease-causing frataxin mutation (W173G)
leads to nonspecific degradation of i-fxn. Thus, the second
of the two processing steps catalyzed by MPP limits
the levels of mature frataxin within mitochondria.
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Comments
© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.