Molecular insights into recognition, activation and function of the atypical chemokine receptor CXCR7/ACKR3. (Doctoral thesis)

Over the last years, the field of research on chemokines and their receptors has made significant progresses. As the crystallography techniques improve, the number of difficult-to-obtain three-dimensional chemokine receptor structures begins to increase. In parallel many, sometimes groundbreaking, functional data have recently been reported. As a consequence, the convictions within the chemokine-receptor community evolve considerably as the previously widely accepted models fail now to withstand the weight of both structural and functional evidences pointing out their oversimplification. The two-site/two-step binding model for chemokine-receptor interactions is being replaced with a more complex, multistep one, the concept of biased signalling is gaining ground and the growing number of novel unsuspected non-chemokine ligands for chemokine receptors regularly refine our understanding on how these receptors work and how they are regulated, bringing about new paradigms. CXCR7, for which two new ligands have recently been discovered and for which the signalling potential, 10 years after its identification as a chemokine receptor, remains a debatable subject, integrates really well in the current changing landscape of the chemokine-receptor field.
The present thesis gathers the fruit of my four years of work as a PhD student at the LIH in the group of Molecular Signalling and Virus-Host Interactions. The aim of my project was to provide new insights into the molecular and structural determinants that dictate CXCR7 ligand recognition and activation, with the final goal to better understand the functions and biology of this atypical and fascinating receptor, how it may affect CXCR4 and CXCR3, with which it shares its ligands and, more generally, the role it may play in the chemokine receptor network.
This thesis will be divided as follows: After a general introduction, the work done for my project will be presented in eight chapters. A short introductory section will precede each chapter, explaining the motivations or goals and the context of the related work. Each chapter will be also followed by a brief concluding section. Chapters 1, 2, 4 and 7 correspond to work already published and a copy of each article is appended at the end of this thesis. Some of the paragraphs have been adapted, taking into account the most recent data. Chapters 5 and 8 correspond to submitted articles, whereas chapter 6 is based on a manuscript currently in preparation. Chapter 3 briefly summarises the preliminary results of an ongoing study that need to be further explored. The final section will be devoted to a short general conclusion allowing to situate the data accumulated during the project in a larger context and suggesting possibilities for follow-up studies.
Although a growing body of evidence indicate that the two-step/two-site binding model is not sufficient to faithfully reflect how chemokines interact with their receptors, it still provides a valuable conceptual framework to understand these interactions and therefore reference to site 1 and site 2 will be regularly made in this thesis. Furthermore, according to the IUPHAR, CXCR7 has recently been officially classified among the atypical chemokine receptors and renamed ACKR3, throughout this work, however, its previous name will be used.