Abstract
Identification of post-translational modifications (PTMs) is important to understanding the biological functions of proteins. MS/MS is a useful tool to identify PTMs. Most existing search tools are restricted to take only a few types of PTMs as input. Here we describe a new algorithm, called MOD(i) (pronounced "mod eye"), that rapidly searches for all known types of PTMs at once without limiting a multitude of modified sites in a peptide. MOD(i) introduces the notion of a tag chain, a combination structure made from multiple sequence tags, that effectively localizes modified regions within a spectrum and overcomes de novo sequencing errors common in tag-based approaches. MOD(i) showed its performance competence by identifying various types of PTMs in analysis of PTM-rich proteins such as glyceraldehyde-3-phosphate dehydrogenase and lens protein. We demonstrated that MOD(i) innovatively manages the computational complexity of identifying multiple PTMs in a peptide, which may exist in a greater variety than usually expected. In addition, it is suggested that MOD(i) has great potential to discover novel modifications.
Highlights
Identification of post-translational modifications (PTMs) is important to understanding the biological functions of proteins
Recent studies indicate that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is distributed throughout the whole cell including nucleus, cytosol, and membrane, plays roles, in addition to glycolysis, in membrane fusion, microtubule bundling, and phosphotransferase activity and is involved in various nuclear processes
These multiple cellular functions of GAPDH can be attributed to the existence of various structures induced in vivo by multiple post-translational modifications recently identified by mass spectrometry using selectively excluded mass screening analysis [18]
Summary
Identification of post-translational modifications (PTMs) is important to understanding the biological functions of proteins. VEMS [7] introduced an improved algorithm to reduce the search space, OpenSea [8] implemented a mass-based sequence alignment between database peptides and de novo interpretation, and TwinPeaks [9] improved the basic scoring scheme of SEQUEST [5], a popular database search program None of these approaches fully addressed the current limitations in the number of PTMs. A few tools were recently introduced for blind PTM search. ModifiComb [12] introduced a ⌬M histogram between unassigned spectra and base peptides found in a database These blind approaches predict PTMs based on the frequency of mass shifts (indicating potential PTMs) in a sample. Our studies with human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) showed that there are many multiply modified peptides in a biological sample
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