Solution structure of CXCL13 and heparan sulfate binding show that GAG binding site and cellular signalling rely on distinct domains

Open Biology
Yoan R MonneauH Lortat-Jacob

Abstract

Chemokines promote directional cell migration through binding to G-protein-coupled receptors, and as such are involved in a large array of developmental, homeostatic and pathological processes. They also interact with heparan sulfate (HS), the functional consequences of which depend on the respective location of the receptor- and the HS-binding sites, a detail that remains elusive for most chemokines. Here, to set up a biochemical framework to investigate how HS can regulate CXCL13 activity, we solved the solution structure of CXCL13. We showed that it comprises an unusually long and disordered C-terminal domain, appended to a classical chemokine-like structure. Using three independent experimental approaches, we found that it displays a unique association mode to HS, involving two clusters located in the α-helix and the C-terminal domain. Computational approaches were used to analyse the HS sequences preferentially recognized by the protein and gain atomic-level understanding of the CXCL13 dimerization induced upon HS binding. Starting with four sets of 254 HS tetrasaccharides, we identified 25 sequences that bind to CXCL13 monomer, among which a single one bound to CXCL13 dimer with high consistency. Importantly, we found tha...Continue Reading

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Citations

Sep 28, 2018·The Journal of Biological Chemistry·Krishna Mohan SepuruKrishna Rajarathnam
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Methods Mentioned

BETA
gel filtration
NMR
chip
flow cytometry
FACS
X-ray
surface plasmon resonance

Software Mentioned

Universal Imaging
VMD
PSVS
SYBYL
GOLD
CNS
CYANA
HADDOCK
ClustalW
SERD

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