MitoFates: improved prediction of mitochondrial targeting sequences and their cleavage sites.
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.
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
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).
Affiliation: From the ‡Department of Computational Biology, Graduate School of Frontier Sciences, The University Tokyo, 5-1-5, Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan;