The Roles of Post-translational Modifications in the Context of Protein Interaction Networks

Abstract

Among other effects, post-translational modifications (PTMs) have been shown to exert their function via the modulation of protein-protein interactions. For twelve different main PTM-types and associated subtypes and across 9 diverse species, we investigated whether particular PTM-types are associated with proteins with specific and possibly “strategic” placements in the network of all protein interactions by determining informative network-theoretic properties. Proteins undergoing a PTM were observed to engage in more interactions and positioned in more central locations than non-PTM proteins. Among the twelve considered PTM-types, phosphorylated proteins were identified most consistently as being situated in central network locations and with the broadest interaction spectrum to proteins carrying other PTM-types, while glycosylated proteins are preferentially located at the network periphery. For the human interactome, proteins undergoing sumoylation or proteolytic cleavage were found with the most characteristic network properties. PTM-type-specific protein interaction network (PIN) properties can be rationalized with regard to the function of the respective PTM-carrying proteins. For example, glycosylation sites were found enriched in proteins with plasma membrane localizations and transporter or receptor activity, which generally have fewer interacting partners. The involvement in disease processes of human proteins undergoing PTMs was also found associated with characteristic PIN properties. By integrating global protein interaction networks and specific PTMs, our study offers a novel approach to unraveling the role of PTMs in cellular processes.

Defining Human Tyrosine Kinase Phosphorylation Networks Using Yeast as an In Vivo Model Substrate

“…When investigating the global yeast interactome we observed clustering of kinase targets in binary and protein complex networks. Phospho-proteins have been shown to cluster in binary networks and on protein complexes in human, as protein networks reflect cellular processes (Beltrao et al, 2012;Woodsmith et al, 2013;Duan and Walther, 2015). Whether clustering is dependent upon individual kinases could not be tested.…”

SUMOylation and phosphorylation cross-talk in hepatocellular carcinoma

“…More than 200 different PTMs were identified in both prokaryotic and eukaryotic cells, that occur in almost all proteins and increase their functional diversity, including ubiquitination, phosphorylation, glycosylation, acetylation, SUMOylation and methylation (4). New tools development to identify PTMs have permitted tremendous advancement in understanding how these important processes are regulated and how they influence protein function in liver pathophysiology.…”

Techniques for the analysis of protein-protein interactions in vivo

“…Equally problematic in heterologous expression systems is the need for correct posttranslational modifications (Duan and Walther, 2015;Hurst and Hemsley, 2015). A plethora of posttranslational modifications are available, such as phosphorylation, glycosylation, and lipidation, all of which depend on recognition of the host organism by the molecular machinery.…”