Evolution, protein-protein interactions, and inhibition mechanisms of ADP-ribosylating tankyrases.

A cell, the smallest unit of life, is estimated to contain millions of proteins. The orchestration of such a gargantuan number of proteins is an incredibly complex task that depends on a plethora of biological processes. ADP-ribosylation is a post-translation modification performed on proteins that directs them to degradation and that modulates various cellular functions. The reaction is catalysed by specific enzymes, including the Diphtheria-toxin like ADP-ribosyltransferases. In this enzyme family, tankyrase 1 and tankyrase 2 are poly-ADP-ribosyltransferases able to transfer multiple ADP-ribose moieties on proteins with the formation of elongated ADP-ribosyl chains. This modification usually results in ubiquitination and degradation of the proteins in the proteasome. Therefore, tankyrases are master regulators of the turnover of a variety of proteins and they influence several cellular processes.
The present thesis provides an extensive study on tankyrases by investigating diverse facets of their biology: origin and evolution, characterization of protein binding partners, and inhibition of catalytic and scaffolding functions. The results indicate that tankyrases originated in choanoflagellates and have conserved their molecular functions in the metazoan lineage. In addition, the re-evaluation of the dual protein- and lipid-phosphatase PTEN reveals that this protein is not a tankyrase partner and substrate. Moreover, this work focuses on the development of novel catalytic inhibitors characterized by a quinazolin-4-one scaffold and the discovery of a new class of potent scaffolding inhibitors selective towards the ARC4 tankyrase domain.