PhD Scientific Days 2026

Poster Session 3.U - Molecular Medicine

Diversity of β-arrestin binding in GPCRs: the role of core and C-terminal interactions

Name of the presenter

Kis, Katalin

Institute/workplace of the presenter

Department of Physiology

Authors

Katalin Kis¹
1: Department of Physiology

Text of the abstract

Introduction
β-arrestins are involved in termination of GPCR signalling (desensitization) and internalization. They bind to receptors in two main ways: via a core interaction to the transmembrane core of the receptor, and via a C-terminal interaction to the phosphorylated intracellular tail region. GPCRs are traditionally classified into class A and B based on the stability of β-arrestin binding. Class A receptors (e.g. β2AR, V1A, CB1) show transient binding, whereas class B receptors (e.g. AT1R, V2R) form stable complexes that internalize into endosomes. The binding preferences of β-arrestin1 and β-arrestin2 isoforms may differ, but the structural basis of this is not fully understood.
Aims
Our aim was to map in detail the β-arrestin binding of different GPCRs. We investigated the role of the core and C-terminal binding interfaces of β-arrestins in numerous GPCRs, as well as how these influence the binding of β-arrestin1 and β-arrestin2 isoforms in class A and B receptors.
Method
We examined activation differences of β-arrestin1/2 isoforms and binding-site mutants in numerous class A and B GPCRs. We performed BRET-based measurements and confocal microscopy in cells expressing wild-type and mutant β-arrestins. Two mutant β-arrestins were used: K2A, which impairs the C-terminal interaction, and ΔFLR, which impairs the core interaction.
Results
The individual mutations reduced β-arrestin activation in certain receptors as expected, but to varying degrees; however, in other cases the loss of one binding interface enhanced recruitment through the other pathway. In some receptors both interaction interfaces were required, and mutation of either binding interface abolished β-arrestin activation.
Conclusion
Our results suggest that GPCRs cannot be simply classified into class A and B based on β-arrestin binding. Even receptors classified into the same class show significant differences: the contribution of core and C-terminal interactions differs and may also interact with each other, even in an inhibitory manner. The different preferences of β-arrestin1 and β-arrestin2 further increase the complexity of the system, suggesting a multi-state binding model.
Funding
This work was supported by the Hungarian National Research, Development, and Innovation Fund (NKFI FK 138862, K 139231).

kis.katalin@semmelweis.hu
Semmelweis University
Supervisors: Gábor Turu, László Hunyady