title: Human proteins with target sites of multiple post-translational modification types are more prone to be involved in disease.
abstract: Many proteins can be modified by multiple types of post-translational modifications (Mtp-proteins). Although some post-translational modifications (PTMs) have recently been found to be associated with life-threatening diseases like cancers and neurodegenerative disorders, the underlying mechanisms remain enigmatic to date. In this study, we examined the relationship of human Mtp-proteins and disease and systematically characterized features of these proteins. Our results indicated that Mtp-proteins are significantly more inclined to participate in disease than proteins carrying no known PTM sites. Mtp-proteins were found significantly enriched in protein complexes, having more protein partners and preferred to act as hubs/superhubs in protein-protein interaction (PPI) networks. They possess a distinct functional focus, such as chromatin assembly or disassembly, and reside in biased, multiple subcellular localizations. Moreover, most Mtp-proteins harbor more intrinsically disordered regions than the others. Mtp-proteins carrying PTM types biased toward locating in the ordered regions were mainly related to protein-DNA complex assembly. Examination of the energetic effects of PTMs on the stability of PPI revealed that only a small fraction of single PTM events influence the binding energy of >2 kcal/mol, whereas the binding energy can change dramatically by combinations of multiple PTM types. Our work not only expands the understanding of Mtp-proteins but also discloses the potential ability of Mtp-proteins to act as key elements in disease development.
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong SAR 852000, China.
authors.forename: Qianli
authors.initials: Q
authors.lastname: Huang
authors.forename: Jinhui
authors.initials: J
authors.lastname: Chang
authors.forename: Man Kit
authors.initials: MK
authors.lastname: Cheung
authors.forename: Wenyan
authors.initials: W
authors.lastname: Nong
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Lee
authors.forename: Hoi Shan
authors.initials: HS
authors.lastname: Kwan
mesh_terms: D020022:Genetic Predisposition to Disease; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058977:Molecular Sequence Annotation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D064267:Intrinsically Disordered Proteins; D020543:Proteome