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Structural Basis of Chemokine Interactions With Heparan Sulfate, Chondroitin Sulfate, and Dermatan Sulfate

Structural Basis of Chemokine Interactions With Heparan Sulfate, Chondroitin Sulfate, and Dermatan Sulfate

Krishna Mohan Sepuru, Krishna Rajarathnam

J Biol Chem. 2019 Oct 25;294(43):15650-15661.

PMID: 31455633

Abstract:

Chemokines play diverse roles in human pathophysiology, ranging from trafficking leukocytes and immunosurveillance to the regulation of metabolism and neural function. Chemokine function is intimately coupled to binding tissue glycosaminoglycans (GAGs), heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS). Currently, very little is known about how the structural features and sequences of a given chemokine, the structure and sulfation pattern of a given GAG, and structural differences among GAGs and among chemokines impact binding interactions. In this study, we used solution NMR spectroscopy to characterize the binding interactions of two related neutrophil-activating chemokines, CXCL1 and CXCL5, with HS, CS, and DS. For both chemokines, the dimer bound all three GAGs with higher affinity than did the monomer, and affinities of the chemokines for CS and DS were lower than for HS. NMR-based structural models reveal diverse binding geometries and show that the binding surfaces for each of the three GAGs were different between the two chemokines. However, a given chemokine had similar binding interactions with CS and DS that were different from HS. Considering the fact that CXCL1 and CXCL5 activate the same CXCR2 receptor, we conclude that GAG interactions play a role in determining the nature of chemokine gradients, levels of free chemokine available for receptor activation, how chemokines bind their receptors, and that differences in these interactions determine chemokine-specific function.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP54328335-A	Dermatan sulfate		54328-33-5	Price

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