title: Single-residue posttranslational modification sites at the N-terminus, C-terminus or in-between: To be or not to be exposed for enzyme access.
abstract: Many protein posttranslational modifications (PTMs) are the result of an enzymatic reaction. The modifying enzyme has to recognize the substrate protein's sequence motif containing the residue(s) to be modified; thus, the enzyme's catalytic cleft engulfs these residue(s) and the respective sequence environment. This residue accessibility condition principally limits the range where enzymatic PTMs can occur in the protein sequence. Non-globular, flexible, intrinsically disordered segments or large loops/accessible long side chains should be preferred whereas residues buried in the core of structures should be void of what we call canonical, enzyme-generated PTMs. We investigate whether PTM sites annotated in UniProtKB (with MOD_RES/LIPID keys) are situated within sequence ranges that can be mapped to known 3D structures. We find that N- or C-termini harbor essentially exclusively canonical PTMs. We also find that the overwhelming majority of all other PTMs are also canonical though, later in the protein's life cycle, the PTM sites can become buried due to complex formation. Among the remaining cases, some can be explained (i) with autocatalysis, (ii) with modification before folding or after temporary unfolding, or (iii) as products of interaction with small, diffusible reactants. Others require further research how these PTMs are mechanistically generated in vivo.
authors.affiliation: Bioinformatics Institute (BII), Agency for Science and Technology (A*STAR), Matrix, Singapore.
authors.forename: Fernanda L
authors.initials: FL
authors.lastname: Sirota
authors.affiliation: Bioinformatics Institute (BII), Agency for Science and Technology (A*STAR), Matrix, Singapore.|School of Biological Sciences (SBS), Nanyang Technological University (NTU), Singapore.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.affiliation: Bioinformatics Institute (BII), Agency for Science and Technology (A*STAR), Matrix, Singapore.
authors.forename: Birgit
authors.initials: B
authors.lastname: Eisenhaber
authors.affiliation: Bioinformatics Institute (BII), Agency for Science and Technology (A*STAR), Matrix, Singapore.|Department of Biological Sciences (DBS), National University of Singapore (NUS), Singapore.|School of Computer Engineering (SCE), Nanyang Technological University (NTU), Singapore.
authors.forename: Frank
authors.initials: F
authors.lastname: Eisenhaber
mesh_terms: D000818:Animals; D055162:Biocatalysis; D030562:Databases, Protein; D006801:Humans; D008055:Lipids / Q000032:analysis; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D040901:Proteomics
chemical_list: D008055:Lipids; D011506:Proteins
keywords: Accessibility; Bioinformatics; Posttranslational modifications; Protein; Structure