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Revealing the mechanism of action of intrinsically disordered proteins in MAPK cell signalling

Lundi 27 novembre 2023 14:00 - Duree : 2 heures
Lieu : Salle de séminiare de l’IBS, 71 avenue des Martyrs, Grenoble

Orateur : Soutenance de Thèse de Thibault ORAND (IBS/Groupe Flexibilité et Dynamique des Protéines par RMN)

L’accès au campus EPN nécessite un avis de rendez-vous. A cet effet merci d’adresser votre demande à ibs.seminaires@ibs.fr (au moins 48h à l’avance).

Résumé :

Intrinsically disordered proteins and regions (IDPs/IDRs) are highly dynamic molecules due to their specific amino acid composition. They play vital roles in biology and are involved in numerous diseases. Understanding their molecular properties and interactions with their protein partners is important given their strong involvement in many fundamental biological processes. Notably, many proteins involved in cell signaling, essential for signal transduction within cells, exhibit high levels of intrinsic disorder. Research has shown that their IDRs are enriched with linear motifs that facilitate interactions with protein partners. However, our structural knowledge so far primarily relies on crystallographic structures, providing an incomplete structural insight. To bridge this gap, the study of IDRs and their interactions in cell signaling is essential. In this regard, the mitogen-activated protein kinase (MAPK) signaling pathways (each pathway including a downstream MAP kinase) offer a means to explore their roles in interactions that ensure specific signal transduction. Indeed, MAPK pathways are vital components of eukaryotic cells and heavily rely on IDRs to assemble multi-kinase complexes competent for signal transduction. Binding motifs (D- and F-motifs) are prevalent within IDRs, facilitating specific interactions of MAP kinases with their partners. There are notably two key types of interactions involving MAPKs, and these motifs ensure signal fidelity : one involves kinase tails recruiting downstream MAPKs, and the other involves scaffold proteins specifically recruiting signaling components of a signaling module, forming specific multi-kinase complexes ensuring precise and regulated pathway activation. Scaffold proteins also act as platforms for post-translational modifications, including phosphorylation, which plays a role in pathway activity regulation.

We initially advanced the understanding of the structural characterization of the scaffold protein JIP1 by studying its interaction with the MAPK JNK1 within the JNK pathway. Using NMR, we obtained an atomic resolution description of the disordered region of JIP1 and also studied its interaction profile with JNK1, revealing several new interactions, including the presence of an F- motif in addition to the previously characterized D-motif, allowing us to propose a structural model of the JIP1 bipartite interaction with JNK1. Furthermore, we studied the JNK1-dependent phosphorylation profile of JIP1’s IDR in real-time using NMR, identifying a significant variation in their phosphorylation rates due to structural constraints imposed by interaction motifs and local sequence preferences. Finally, we combined NMR with isothermal titration calorimetry to demonstrate that the D-motif of MKK4 IDR, an activator of p38α and JNK1, interacts with similar affinities with these two kinases by adopting distinct conformations, explained by unique structural properties on their surfaces modulating the specific binding conformation with MKK4. MKK4 employs an entropic-enthalpic compensation strategy to bind to JNK1 by adopting a local helical fold. In summary, this thesis work provides crucial insights into the role of protein disorder in the specific assembly and regulation of MAPK signaling complexes, and demonstrates how powerful NMR is to study systems involving high levels of protein disorder.

Contact : ibs.seminaires@ibs.fr

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