Computational Prediction of Post-Translational Modification Sites in Proteins

Abstract

The last several decades have witnessed rapid progresses in identification and functional analysis of post-translational modifications (PTMs) in proteins. Through temporal and spatial modification of proteins by covalent attachment of additional chemical groups and other small proteins, proteolytic cleavage or intein splicing, PTMs greatly expand the proteome diversity and play important roles in regulating the stability and functions of the proteins (Mann and Jensen, 2003; Walsh, 2005; Walsh and Jefferis, 2006). To date, more than 350 types of distinct PTMs were experimentally discovered in vivo, while subsequently functional assays have detected a number of exciting observations. In 1992, the Nobel Prize in Physiology or Medicine was awarded to Edmond H. Fischer and Edwin G. Krebs for their seminal discovery that reversible protein phosphorylation is a biological regulatory mechanism (Kresge et al., 2011), while Leland H. Hartwell, Tim Hunt, and Paul M. Nurse shared the Nobel Prize in Physiology or Medicine 2001 for their profound contributions in identification of key regulators including cyclin-dependent kinases (CDKs) and cyclins that precisely orchestrate the cell cycle process through phosphorylation (Balter and Vogel, 2001). Moreover, Aaron Ciechanover, Avram Hershko and Irwin Rose became laureates of the Nobel Prize in Chemistry 2004 for their discovery of ubiquitin-mediated protein degradation (Vogel, 2004). Although virtually all PTMs play their major roles as regulating the biological processes, different ones have their aspects with emphasis. For example, phosphorylation is preferentially implicated in signal-transduction cascades, while ubiquitination regulates the lifetime of proteins by targeting specific substrates for degradation. Recently, protein lysine acetylation was observed to play a predominant role in regulation of cellular metabolism (Wang et al., 2010; Zhao et al., 2010). Other types of PTMs such as sumoylation, glycosylation and palmitoylation are also critical for exactly orchestrating distinct cellular processes (Fukata and Fukata, 2010; Linder and Deschenes, 2007). Furthermore, the crosstalk among different PTMs is ubiquitous, especially on histones, which is regarded as the “histone code” (Jenuwein and Allis, 2001). The aberrances of PTMs are highly associated in diseases and cancers, while a variety of regulatory enzymes involved in PTMs have been drug targets (Lahiry et al., 2010; Norvell and McMahon, 2010). In this regard, elucidation of PTMs regulatory roles is fundamental for understanding molecular mechanisms of diseases and cancers, and further biomedical design.