Structure and Dynamics of Human Chemokine CCL16—Implications for Biological Activity

Abstract

Human C-C motif ligand 16 (CCL16) is a chemokine that is distinguished by a large cleavable C-terminal extension of unknown significance. Conflicting data have been reported concerning its tissue distribution and modulation of expression, rendering the biological function of CCL16 enigmatic. Here, we report an integrated approach to the characterisation of this chemokine, including a re-assessment of its expression characteristics as well as a biophysical investigation with respect to its structure and dynamics. Our data indicate that CCL16 is chiefly synthesised by hepatocytes, without an appreciable response to mediators of inflammation, and circulates in the blood as a full-length protein. While the crystal structure of CCL16 confirms the presence of a canonical chemokine domain, molecular dynamics simulations support the view that the C-terminal extension impairs the accessibility of the glycosaminoglycan binding sites and may thus serve as an intrinsic modulator of biological activity.

Structural basis of chemokine recognition by the class A3 tick evasin EVA‐ACA1001

“…Consequently, the strands labeled β3–β7 in EVA‐1, EVA‐P974, and EVA‐AAM1001 are labeled β1–β5, respectively, in EVA‐ACA1001. CCL16 adopts the canonical chemokine architecture, which consists of three β‐strands and an α‐helix linked via two conserved disulfide bonds to the disordered N‐terminus, the CC motif, and the irregularly‐structured “N‐loop” (Figure 6a ) (Weiergräber et al, 2022 ). EVA‐ACA1001 interacts with the chemokine CC motif, the residue immediately following the CC motif (“CC + 1” residue), and a shallow groove between the N‐loop and the third β‐strand (β3).…”