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Title: Functional analysis of poly-ubiquitin chains in immune signalling
Author: Morris-Davies, A. C.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2013
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NF-κB transcription factors play essential roles in regulating the expression of a large array of genes involved in immune and inflammatory responses, cell proliferation, apoptosis and oncogenesis. In recent years, ubiquitination of key components has emerged as a crucial regulatory mechanism in NF-κB signalling pathways. This can either directly modulate the activity of the target substrate or provide a scaffold for the recognition and recruitment of other signalling molecules via their respective ubiquitin binding domains. NEMO, the regulatory subunit of the IKK complex, is a prime example of a signalling component which interacts with ubiquitin chains of different topologies as well as being modified by ubiquitination. These events are thought to regulate the activation of the kinase subunits of the complex, IKKα and IKKβ, which ultimately results in liberation of NF-κB and translocation to the nucleus. NEMO itself possesses two ubiquitin-binding domains: the CoZi/UBAN domain and a C-terminal zinc finger (ZF). The work presented in this thesis shows that the synergistic action of these two domains confers specificity for K63-linked ubiquitin chains. Importantly, chain length plays a crucial role in these binding events. The discovery that NEMO becomes modified by the E3 ligase LUBAC with a novel type of ubiquitin chain, termed linear, opened up a whole new exciting area of research. So far, LUBAC is the only E3 ligase known to synthesize this type of chain. This thesis provides a first glimpse into the mechanistic determinants which allow LUBAC to enforce the formation of linear ubiquitin chains and demonstrates, for the first time, that one of its subunits, HOIL-1L, transfers ubiquitin to a substrate via a thioester intermediate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available