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MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites.

Fukasawa Y, Tsuji J, Fu SC, Tomii K, Horton P, Imai K - Mol. Cell Proteomics (2015)

Bottom Line: Here we describe MitoFates, an improved prediction method for cleavable N-terminal mitochondrial targeting signals (presequences) and their cleavage sites.Interestingly, these include candidate regulators of parkin translocation to damaged mitochondria, and also many genes with known disease mutations, suggesting that careful investigation of MitoFates predictions may be helpful in elucidating the role of mitochondria in health and disease.MitoFates is open source with a convenient web server publicly available.

View Article: PubMed Central - PubMed

Affiliation: From the ‡Department of Computational Biology, Graduate School of Frontier Sciences, The University Tokyo, 5-1-5, Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan;

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Positively charged amphiphilicity (PA) score and presequence specific motifs.A, Histograms of the distribution of maximum hydrophobic moment score (above) and PA score (below) in the N-terminal 30 residues of proteins with and without a presequence. B, The top six presequence specific hexamers are listed with their statistical significance, coverage in the positive, and negative training examples, PA score, and a sequence logo depicting their matches in the positive data. Arrows show the hydrophobic moments. Blue and gray indicate higher or lower PA score than the 90th percentile score over all hexamers in the positive and negative examples, respectively.
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Figure 3: Positively charged amphiphilicity (PA) score and presequence specific motifs.A, Histograms of the distribution of maximum hydrophobic moment score (above) and PA score (below) in the N-terminal 30 residues of proteins with and without a presequence. B, The top six presequence specific hexamers are listed with their statistical significance, coverage in the positive, and negative training examples, PA score, and a sequence logo depicting their matches in the positive data. Arrows show the hydrophobic moments. Blue and gray indicate higher or lower PA score than the 90th percentile score over all hexamers in the positive and negative examples, respectively.

Mentions: Although the ability to adopt an amphiphilic α-helix has been proposed to be important for presequence recognition (9, 47), prior to this work, attempts to use this feature for prediction have had limited success (16). To investigate this problem, we compared the distributions of maximum hydrophobic moment score (29) in the first 30, 60, and 90 N-terminal residues of proteins containing or lacking presequences. The distributions differ the most in the N-terminal 30 residues, but still overlap each other to a large extent (Fig. 3A, top). We considered one reason for this poor separation may be that the hydrophobic moment calculation does not distinguish between positive and negative charges on the polar face. Given that Tom20 and Tom22 in the TOM complex most likely recognize an amphiphilic helical local structure consisting of hydrophobic and positively charged faces (6, 12, 13), we conjectured that a score that favors positive charges on the polar face might better characterize presequences. Thus, we defined the PA score (Positively charged Amphiphilicity score) that adds a positive charge moment to the hydrophobicity moment as described under “Experimental Procedures” above. This PA score yields much better discrimination (Fig. 3A, bottom). We also note known Tom20 binding sites in the presequences Su9 of N.crassa (48) and ALDH2 of R.norvegicus (12) exhibit a high PA score (data not shown).


MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites.

Fukasawa Y, Tsuji J, Fu SC, Tomii K, Horton P, Imai K - Mol. Cell Proteomics (2015)

Positively charged amphiphilicity (PA) score and presequence specific motifs.A, Histograms of the distribution of maximum hydrophobic moment score (above) and PA score (below) in the N-terminal 30 residues of proteins with and without a presequence. B, The top six presequence specific hexamers are listed with their statistical significance, coverage in the positive, and negative training examples, PA score, and a sequence logo depicting their matches in the positive data. Arrows show the hydrophobic moments. Blue and gray indicate higher or lower PA score than the 90th percentile score over all hexamers in the positive and negative examples, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Positively charged amphiphilicity (PA) score and presequence specific motifs.A, Histograms of the distribution of maximum hydrophobic moment score (above) and PA score (below) in the N-terminal 30 residues of proteins with and without a presequence. B, The top six presequence specific hexamers are listed with their statistical significance, coverage in the positive, and negative training examples, PA score, and a sequence logo depicting their matches in the positive data. Arrows show the hydrophobic moments. Blue and gray indicate higher or lower PA score than the 90th percentile score over all hexamers in the positive and negative examples, respectively.
Mentions: Although the ability to adopt an amphiphilic α-helix has been proposed to be important for presequence recognition (9, 47), prior to this work, attempts to use this feature for prediction have had limited success (16). To investigate this problem, we compared the distributions of maximum hydrophobic moment score (29) in the first 30, 60, and 90 N-terminal residues of proteins containing or lacking presequences. The distributions differ the most in the N-terminal 30 residues, but still overlap each other to a large extent (Fig. 3A, top). We considered one reason for this poor separation may be that the hydrophobic moment calculation does not distinguish between positive and negative charges on the polar face. Given that Tom20 and Tom22 in the TOM complex most likely recognize an amphiphilic helical local structure consisting of hydrophobic and positively charged faces (6, 12, 13), we conjectured that a score that favors positive charges on the polar face might better characterize presequences. Thus, we defined the PA score (Positively charged Amphiphilicity score) that adds a positive charge moment to the hydrophobicity moment as described under “Experimental Procedures” above. This PA score yields much better discrimination (Fig. 3A, bottom). We also note known Tom20 binding sites in the presequences Su9 of N.crassa (48) and ALDH2 of R.norvegicus (12) exhibit a high PA score (data not shown).

Bottom Line: Here we describe MitoFates, an improved prediction method for cleavable N-terminal mitochondrial targeting signals (presequences) and their cleavage sites.Interestingly, these include candidate regulators of parkin translocation to damaged mitochondria, and also many genes with known disease mutations, suggesting that careful investigation of MitoFates predictions may be helpful in elucidating the role of mitochondria in health and disease.MitoFates is open source with a convenient web server publicly available.

View Article: PubMed Central - PubMed

Affiliation: From the ‡Department of Computational Biology, Graduate School of Frontier Sciences, The University Tokyo, 5-1-5, Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan;

Show MeSH