Processing of the N termini of nascent polypeptide chains requires deformylation prior to methionine removal 1 1Edited by M. Gottesman

Solbiati, José O.; Chapman-Smith, Anne; Miller, Judith; Miller, Charles G.; Cronan, John E.

doi:10.1006/jmbi.1999.2913

Cited by 146 publications

(124 citation statements)

References 32 publications

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“…2). As the function of PDF is to facilitate MAP activity (52), these data indicate the genetic and functional linkage of the two components of mitochondrial NME in animals. Finally, it was recently shown that the PDF gene is part of a cluster that is tightly regulated in skeletal muscle regeneration in mice (53), with down-regulation after injury and up-regulation during cell differentiation and re-entry into the cell cycle (see H3113G11 in cluster 7).…”

Section: Discussionmentioning

confidence: 78%

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

Serero

Giglione

Sardini

et al. 2003

Journal of Biological Chemistry

126

137

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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.

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Section: Discussionmentioning

confidence: 78%

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

Serero

Giglione

Sardini

et al. 2003

Journal of Biological Chemistry

126

137

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“…Synthetic peptides with Met-O at the N-terminal position either are not substrates for MAP (37) or are much poorer substrates than the corresponding Met peptide (38). Studies on the effect of H 2 O 2 on protein oxidation in neutrophils showed that Met residues in nascent protein chains were more sensitive to oxidation than were Met residues in a mature protein (39).…”

Section: Discussionmentioning

confidence: 99%

Peptide methionine sulfoxide reductase fromEscherichia coliandMycobacterium tuberculosisprotects bacteria against oxidative damage from reactive nitrogen intermediates

John

Brot

Ruan

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

191

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Inducible nitric oxide synthase (iNOS) plays an important role in host defense. Macrophages expressing iNOS release the reactive nitrogen intermediates (RNI) nitrite and S-nitrosoglutathione (GSNO), which are bactericidal in vitro at a pH characteristic of the phagosome of activated macrophages. We sought to characterize the active intrabacterial forms of these RNI and their molecular targets. Peptide methionine sulfoxide reductase (MsrA; EC 1.8.4.6) catalyzes the reduction of methionine sulfoxide (Met-O) in proteins to methionine (Met). E. coli lacking MsrA were hypersensitive to killing not only by hydrogen peroxide, but also by nitrite and GSNO. The wild-type phenotype was restored by transformation with plasmids encoding msrA from E. coli or M. tuberculosis, but not by an enzymatically inactive mutant msrA, indicating that Met oxidation was involved in the death of these cells. It seemed paradoxical that nitrite and GSNO kill bacteria by oxidizing Met residues when these RNI cannot themselves oxidize Met. However, under anaerobic conditions, neither nitrite nor GSNO was bactericidal. Nitrite and GSNO can both give rise to NO, which may react with superoxide produced by bacteria during aerobic metabolism, forming peroxynitrite, a known oxidant of Met to Met-O. Thus, the findings are consistent with the hypotheses that nitrite and GSNO kill E. coli by intracellular conversion to peroxynitrite, that intracellular Met residues in proteins constitute a critical target for peroxynitrite, and that MsrA can be essential for the repair of peroxynitrite-mediated intracellular damage.

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“…Indeed, stable cognate codonanticodon interaction at this position has been proposed to be important for preventing premature peptidyl-tRNA drop-off (26). Furthermore, the first few N-terminal amino acids modulate the stability of proteins as well as providing determinants for the cleavage of the N-terminal formyl-methionine residue from nascent peptide (28,29). Collectively, this suggests that accurate decoding at the second position is important for gene expression, and therefore bacteria must have developed a mechanism to ensure accurate decoding at the A-site in the absence of an E-tRNA.…”

mentioning

confidence: 99%

Shine–Dalgarno interaction prevents incorporation of noncognate amino acids at the codon following the AUG

Giacco

Márquez

Qin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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During translation, usually only one in Ϸ400 misincorporations affects the function of a nascent protein, because only chemically similar near-cognate amino acids are misincorporated in place of the cognate one. The deleterious misincorporation of a chemically dissimilar noncognate amino acid during the selection process is precluded by the presence of a tRNA at the ribosomal E-site. However, the selection of first aminoacyl-tRNA, directly after initiation, occurs without an occupied E-site, i.e., when only the P-site is filled with the initiator tRNA and thus should be highly error-prone. Here, we show how bacterial ribosomes have solved this accuracy problem: In the absence of a Shine-Dalgarno (SD) sequence, the first decoding step at the A-site after initiation is extremely error-prone, even resulting in the significant incorporation of noncognate amino acids. In contrast, when a SD sequence is present, the incorporation of noncognate amino acids is not observed. This is precisely the effect that the presence of a cognate tRNA at the E-site has during the elongation phase. These findings suggest that during the initiation phase, the SD interaction functionally compensates for the lack of codon-anticodon interaction at the E-site by reducing the misincorporation of near-cognate amino acids and prevents noncognate misincorporation. E-site ͉ translational errorsT he binding of aminoacyl-tRNAs to the ribosome is dictated by the complementarity between the anticodon of the tRNA and the codon of the mRNA. To ensure the high fidelity of translation, the correct stereochemistry of the mRNA-tRNA codon-anticodon interaction is monitored by components of the small ribosomal subunit in a process known as decoding (reviewed in ref. 1). During decoding, the first and second nucleotide positions (in terms of the codon) of the mRNA-tRNA duplex are closely monitored, whereas interaction at the third or wobble position is less strictly recognized. Consistently, the misincorporation of the wrong amino acids into polypeptide chains usually occurs through the binding of nearcognate aminoacyl-tRNAs, i.e., those tRNAs carrying an anticodon similar to that of the cognate aminoacyl-tRNA, rather than noncognate aminoacyl-tRNAs, which carry dissimilar anticodons. Nascent polypeptide chains are surprisingly tolerant to misincorporation, with only one in Ϸ400 misincorporations being deleterious for the protein's activity (reviewed in ref.2). The reason for this is that usually near-cognate aminoacyl-tRNAs are selected instead of the cognate aminoacyl-tRNA, and the genetic code lexicon is organized in such a way that near-cognate tRNAs bear amino acids that are chemically similar to those carried by the cognate tRNA. For example, the misincorporation of an aspartate (codon: GAU/C) by near-cognate Asp-tRNA, instead of glutamate (GAA/G) by the cognate Glu-tRNA, both incorporate acidic amino acids. The middle and, in most cases, the first position of a codon are almost never misread, even under error-inducing conditions such as high magnesiu...

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Processing of the N termini of nascent polypeptide chains requires deformylation prior to methionine removal 1 1Edited by M. Gottesman

Cited by 146 publications

References 32 publications

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

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

Peptide methionine sulfoxide reductase fromEscherichia coliandMycobacterium tuberculosisprotects bacteria against oxidative damage from reactive nitrogen intermediates

Shine–Dalgarno interaction prevents incorporation of noncognate amino acids at the codon following the AUG

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