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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.