title: Ubiquitin chain specific auto-ubiquitination triggers sustained oscillation, bistable switches and excitable firing.
abstract: Ubiquitin modification of cellular proteins commonly targets them for proteosomal degradation, but can also convey non-proteolytic functions. Over the past years, advances in experimental approaches have helped uncover the extensive involvement of ubiquitination in protein regulation. However, our understanding of the dynamics of the ubiquitination-related networks have lagged behind. A common regulatory theme for many E3 ligases is the ability to self-catalyse their own ubiquitination without involving external E3 ligating enzymes. Here, the authors have explored computational models of both proteolytic and non-proteolytic auto-ubiquitination of E3 ligases and characterised the dynamic properties of these regulatory motifs. Remarkably, in both cases auto-ubiquitination coupled with multi-step de-ubiquitination process can bring about sustained oscillatory behaviour. In addition, the same basic wiring structures can trigger bistable switches of activity and excitable firing of the dynamic responses of the ubiquitinated E3 ligase. Bifurcation analysis allows one to derive parametric conditions that govern these dynamics. They also show that these complex non-linear behaviours persist for a more detailed mechanistic description that involves the E1 and E2 enzymes. Their work therefore provides new insights into the dynamic features of auto-ubiquitination in different cellular contexts.
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland. lan.nguyen@ucd.ie.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.affiliation: Department of Physics and Institute of Theoretical Physics and Astrophysics, Xiamen University, Xiamen 361005, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Thawfeek M
authors.initials: TM
authors.lastname: Varusai
authors.affiliation: School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland. boris.kholodenko@ucd.ie.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
mesh_terms: D007700:Kinetics; D008954:Models, Biological; D059748:Proteolysis; D049490:Systems Biology; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases