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J. Biol. Chem., Vol. 278, Issue 52, 52953-52963, December 26, 2003

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An Unusual Peptide Deformylase Features in the Human Mitochondrial N-terminal Methionine Excision Pathway^*

Alexandre Serero, Carmela Giglione, Alessandro Sardini¶, Juan Martinez-Sanz, and Thierry Meinnel||

From the Protein Maturation Group, Institut des Sciences du Végétal, UPR2355, Centre National de la Recherche Scientifique, Bâtiment 23, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette cedex, France and the ^¶Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Rd., London W12 0NN, United Kingdom

Dedicated machinery for N-terminal methionine excision (NME) was recently identified in plant organelles and shown to be essential in plastids. We report here the existence of mitochondrial NME in mammals, as shown by the identification of cDNAs encoding specific peptide deformylases (PDFs) and new methionine aminopeptidases (MAP1D). We cloned the two full-length human cDNAs and showed that the N-terminal domains of the encoded enzymes were specifically involved in targeting to mitochondria. In contrast to mitochondrial MAP1D, the human PDF sequence differed from that of known PDFs in several key features. We characterized the human PDF fully in vivo and in vitro. Comparison of the processed human enzyme with the plant mitochondrial PDF1A, to which it is phylogenetically related, showed that the human enzyme had an extra N-terminal domain involved in both mitochondrial targeting and enzyme stability. Mammalian PDFs also display non-random substitutions in the conserved motifs important for activity. Human PDF site-directed mutagenesis variants were studied and compared with the corresponding plant PDF1A variants. We found that amino acid substitutions in human PDF specifically altered its catalytic site, resulting in an enzyme intermediate between bacterial PDF1Bs and plant PDF1As. Because (i) human PDF was found to be active both in vitro and in vivo, (ii) the entire machinery is conserved and expressed in most animals, (iii) the mitochondrial genome expresses substrates for these enzymes, and (iv) mRNA synthesis is regulated, we conclude that animal mitochondria have a functional NME machinery that can be regulated.

Received for publication, September 3, 2003 , and in revised form, October 1, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY368205 and AY374142.

^* This work was supported by an Action Thématique et Incitative sur Programme grant from the C.N.R.S. (to T. M.) and by Grant 4477 from the Association pour la Recherche sur le Cancer (ARC, Villejuif). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Materials.

Supported by a Ph.D. Thesis scholarship from the French Ministère de l'Education Nationale, de la Recherche et de la Technologie.

^|| To whom correspondence should be addressed. Tel.: 33-1-69-82-36-12; Fax: 33-1-69-82-36-07; E-mail: meinnel{at}isv.cnrs-gif.fr.

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