Around 30 years ago, the discovery of modular protein domains began to change the scientific world’s view on cell signalling. The multitude of ground-breaking discoveries in this field over the past three decades increased fundamentally the understanding of cellular signal transduction and how proteins transmit extra- and intracellular signals in this context. The SH3 domain was one of the first described modular protein domains and was soon found to be involved in numerous important cellular functions and signalling cascades. Moreover, SH3 domain-mediated interactions were also found to be hijacked by pathogens, especially viruses, which developed highly specific proteins mimicking cellular SH3 domain ligands. This molecular mimicry allows the virus to interfere, manipulate and exploit host cellular signalling for its own benefits and survival. The vital elements of this doctoral thesis are the identification and characterization of so far unknown, high-affinity SH3 domain-mediated interactions and in the context of pathogenic SH3 domain ligand origin, also the elucidation of functional consequences for the host cell. The first part describes a large-scale screening approach uncovering high-affinity interactions between human SH3 domains and potential native target proteins. The identified robust SH3-mediated interactions are novel and thereby provide a valuable resource for future research. The second part extends the focus to SH3-mediated interactions between viruses and their host cells. These interactions are of exceptional impact since they enable the virus to manipulate or hijack the host’s immune defence system and thereby promote viral survival and propagation. Two examples of viral proteins binding via an SH3-mediated interaction to host cell factors are presented in this thesis: - the interaction of influenza A virus (IAV) NS1 protein with host cell Crk-adaptor proteins in context of reorganizing the Crk(L)-PI3 kinase signalling complex and – the interaction between molluscum contagiosum virus (MCV) MC159 protein and host cell SH3 binding protein 4 (SH3BP4). The study addressing the reorganization of the Crk(L)-PI3 kinase signalling complex by NS1, focuses on structural and biochemical aspects of a newly discovered trimeric protein complex and the related functional changes in downstream signalling, such as Akt activation. The work presented on MC159 identifies host cell SH3BP4 as a new target protein of MCV and shows that the SH3-mediated interaction between MC159 and SH3BP4 is essential for suppression of cellular autophagy by MC159.
|Tila||Julkaistu - 2019|
|OKM-julkaisutyyppi||G5 Tohtorinväitöskirja (artikkeli)|
LisätietojaM1 - 91 s. + liitteet
- 3111 Biolääketieteet
- 1183 Kasvibiologia, mikrobiologia, virologia