Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Tuesday Speaker Abstracts

Ligand-specific Conformational Changes in CCR7 Coupled to Selecting Different Signaling Pathways upon CCL19 and CCL21 Ligand Binding

Dimitrios Morikis , Zied Gaieb, David Lo. University of California, Riverside, CA, USA.

Chemokine receptor type 7 (CCR7) is a G protein-coupled receptor (GPCR) that is activated by ligands CCL19 and CCL21. The ligands are expressed in different parts of the body as gradients to aid in homing of T cells and antigen-presenting dendritic cells to the lymph nodes. Although both ligands have similar structures and activate the same receptor (CCR7), they induce distinct signaling pathways. While both ligands mediate their signaling through G-protein and GRK6, only CCL19 induces CCR7 desensitization and internalization through phosphorylation by GRK3 and recruitment of β-arrestin. The functional diversity of receptor-ligand binding is related to decoupled or partially decoupled conformational changes. We will present the results of molecular dynamics (MD) simulations of free CCR7 and the complexes CCR7-CCL19 and CCR7-CCL21. We will discuss long-range conformational changes associated with receptor activation pathways upon ligand binding. Differences in the conformational changes of the three systems are quantitatively assessed with a range of MD analysis methods, including principal component analysis (PCA) and dynamic cross-correlation analysis (DCC). We observe that the presence of the ligands introduces collective motions within larger CCR7 domains, including trans-membrane helices and intra-cellular loops. Such motions may be necessary to induce large openings between intra-cellular regions that are necessary to accommodate G protein binding and to initiate intra-cellular signaling pathways. This work aims to delineate the structural elements that are responsible for biased receptor activation, and the conformational changes and long-range motions that link extra-cellular ligand binding with intra-cellular protein binding and selection of signaling pathways.

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