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Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3.

Liang, WG; Triandafillou, CG; Huang, TY; Zulueta, MM; Banerjee, S; Dinner, AR; Hung, SC; (2016) Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3. PNAS - Proceedings of The National Academy of Sciences of The United States of America , 113 (18) pp. 5000-5005. 10.1073/pnas.1523981113. Green open access

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Abstract

CC chemokine ligand 5 (CCL5) and CCL3 are critical for immune surveillance and inflammation. Consequently, they are linked to the pathogenesis of many inflammatory conditions and are therapeutic targets. Oligomerization and glycosaminoglycan (GAG) binding of CCL5 and CCL3 are vital for the functions of these chemokines. Our structural and biophysical analyses of human CCL5 reveal that CCL5 oligomerization is a polymerization process in which CCL5 forms rod-shaped, double-helical oligomers. This CCL5 structure explains mutational data and offers a unified mechanism for CCL3, CCL4, and CCL5 assembly into high-molecular-weight, polydisperse oligomers. A conserved, positively charged BBXB motif is key for the binding of CC chemokines to GAG. However, this motif is partially buried when CCL3, CCL4, and CCL5 are oligomerized; thus, the mechanism by which GAG binds these chemokine oligomers has been elusive. Our structures of GAG-bound CCL5 and CCL3 oligomers reveal that these chemokine oligomers have distinct GAG-binding mechanisms. The CCL5 oligomer uses another positively charged and fully exposed motif, KKWVR, in GAG binding. However, residues from two partially buried BBXB motifs along with other residues combine to form a GAG-binding groove in the CCL3 oligomer. The N termini of CC chemokines are shown to be involved in receptor binding and oligomerization. We also report an alternative CCL3 oligomer structure that reveals how conformational changes in CCL3 N termini profoundly alter its surface properties and dimer-dimer interactions to affect GAG binding and oligomerization. Such complexity in oligomerization and GAG binding enables intricate, physiologically relevant regulation of CC chemokine functions.

Type: Article
Title: Structural basis for oligomerization and glycosaminoglycan binding of CCL5 and CCL3.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1523981113
Publisher version: http://doi.org/10.1073/pnas.1523981113
Language: English
Additional information: Copyright © 2017 The Author(s). All rights reserved.
Keywords: CC chemokine, X-ray crystallography, glycosaminoglycan, protein oligomerization, signal transduction, Binding Sites, Chemokine CCL3, Chemokine CCL5, Dimerization, Glycosaminoglycans, Humans, Protein Binding, Protein Conformation, Structure-Activity Relationship
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1503793
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