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Contribution of the putative heparan sulfate-binding motif BBXB of RANTES to transendothelial migration

Lookup NU author(s): Professor Simi Ali, Sarah Fritchley, Dr Benjamin Chaffey, Emeritus Professor John Kirby

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Abstract

The chemokines are a family of small chemoattractant proteins that have a range of functions, including activation and promotion of vectorial migration of leukocytes. Regulation on activation, normal T cell expressed and secreted (RANTES; CCL5), a member of the CC-chemokine subfamily, has been implicated in a variety of immune responses. In addition to the interaction of CC-chemokines with their cognate cell-surface receptors, it is known that they also bind to glycosaminoglycans (GAGs), including heparan sulfate. This potential for binding to GAG components of proteoglycans on the cell surface or within the extracellular matrix might allow formation of the stable chemokine concentration gradients necessary for leukocyte chemotaxis. In this study, we created a panel of mutant RANTES molecules containing neutral amino acid substitutions within putative, basic GAG-binding domains. Despite showing reduced binding to GAGs, it was found that each mutant containing a single amino acid substitution induced a similar leukocyte chemotactic response within a concentration gradient generated by free solute diffusion. However, we found that the mutant K45A had a significantly reduced potential to stimulate chemotaxis across a monolayer of microvascular endothelial cells. Significantly, this mutant bound to the CCR5 receptor and showed a potential to mobilize Ca2+ with an affinity similar to the wild-type protein. These results show that the interaction between RANTES and GAGs is not necessary for specific receptor engagement, signal transduction, or leukocyte migration. However, this interaction is required for the induction of efficient chemotaxis through the extracellular matrix between confluent endothelial cells.


Publication metadata

Author(s): Fritchley SJ; Kirby JA; Ali S; Chaffey BT

Publication type: Article

Publication status: Published

Journal: Glycobiology

Year: 2002

Volume: 12

Issue: 9

Pages: 535-543

ISSN (print): 0959-6658

ISSN (electronic): 1460-2423

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/glycob/cwf069

DOI: 10.1093/glycob/cwf069


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