Faculty Collaboration Database

The dependence of chemokine-glycosaminoglycan interactions on chemokine oligomerization. Glycobiology 2016 Mar;26(3):312-26

Date

11/20/2015

Pubmed ID

26582609

Pubmed Central ID

PMC4736540

DOI

10.1093/glycob/cwv100

Scopus ID

2-s2.0-84959429965 (requires institutional sign-in at Scopus site)   82 Citations

Abstract

Both chemokine oligomerization and binding to glycosaminoglycans (GAGs) are required for their function in cell recruitment. Interactions with GAGs facilitate the formation of chemokine gradients, which provide directional cues for migrating cells. In contrast, chemokine oligomerization is thought to contribute to the affinity of GAG interactions by providing a more extensive binding surface than single subunits alone. However, the importance of chemokine oligomerization to GAG binding has not been extensively quantified. Additionally, the ability of chemokines to form different oligomers has been suggested to impart specificity to GAG interactions, but most studies have been limited to heparin. In this study, several differentially oligomerizing chemokines (CCL2, CCL3, CCL5, CCL7, CXCL4, CXCL8, CXCL11 and CXCL12) and select oligomerization-deficient mutants were systematically characterized by surface plasmon resonance to determine their relative affinities for heparin, heparan sulfate (HS) and chondroitin sulfate-A (CS-A). Wild-type chemokines demonstrated a hierarchy of binding affinities for heparin and HS that was markedly dependent on oligomerization. These results were corroborated by their relative propensity to accumulate on cells and the critical role of oligomerization in cell presentation. CS-A was found to exhibit greater chemokine selectivity than heparin or HS, as it only bound a subset of chemokines; moreover, binding to CS-A was ablated with oligomerization-deficient mutants. Overall, this study definitively demonstrates the importance of oligomerization for chemokine-GAG interactions, and demonstrates diversity in the affinity and specificity of different chemokines for GAGs. These data support the idea that GAG interactions provide a mechanism for fine-tuning chemokine function.

Author List

Dyer DP, Salanga CL, Volkman BF, Kawamura T, Handel TM

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Binding Sites
Cell Movement
Chemokines
Glycosaminoglycans
Heparin
Heparitin Sulfate
Models, Molecular
Protein Binding
Protein Conformation
Protein Structure, Tertiary
Surface Plasmon Resonance