The N-terminal region of the atypical chemokine receptor ACKR2 is a key determinant of ligand binding

Hewit, K. D., Fraser, A., Nibbs, R. J.B. and Graham, G. J. (2014) The N-terminal region of the atypical chemokine receptor ACKR2 is a key determinant of ligand binding. Journal of Biological Chemistry, 289(18), pp. 12330-12342. (doi: 10.1074/jbc.M113.534545)

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Abstract

The atypical chemokine receptor, ACKR2 is a pivotal regulator of chemokine-driven inflammatory responses and works by binding, internalizing, and degrading inflammatory CC-chemokines. ACKR2 displays promiscuity of ligand binding and is capable of interacting with up to 14 different inflammatory CC-chemokines. Despite its prominent biological role, little is known about the structure/function relationship within ACKR2, which regulates ligand binding. Here we demonstrate that a conserved tyrosine motif at the N terminus of ACKR2 is essential for ligand binding, internalization, and scavenging. In addition we demonstrate that sulfation of this motif contributes to ligand internalization. Furthermore, a peptide derived from this region is capable of binding inflammatory chemokines and inhibits their interaction with their cognate signaling receptors. Importantly, the peptide is only active in the sulfated form, further confirming the importance of the sulfated tyrosines for function. Finally, we demonstrate that the bacterial protease, staphopain A, can cleave the N terminus of ACKR2 and suppress its ligand internalization activity. Overall, these results shed new light on the nature of the structural motifs in ACKR2 that are responsible for ligand binding. The study also highlights ACKR2-derived N-terminal peptides as being of potential therapeutic significance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fraser, Dr Alasdair and Nibbs, Professor Rob and Hewit, Dr Kay and Graham, Professor Gerard
Authors: Hewit, K. D., Fraser, A., Nibbs, R. J.B., and Graham, G. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Copyright Holders:Copyright © 2014 American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Biological Chemistry 289(18):12330-12342
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514422Regulation of the adaptive immune response by chemokine scavenging receptorsGerard GrahamMedical Research Council (MRC)G0901113III -IMMUNOLOGY