TY - JOUR
T1 - Structural basis of a chemokine heterodimer binding to glycosaminoglycans
AU - Sepuru, Krishna Mohan
AU - Rajarathnam, Krishna
N1 - Publisher Copyright:
© 2021 The Author(s).
PY - 2021/3
Y1 - 2021/3
N2 - Chemokines Cxcl1/KC and Cxcl2/MIP2 play a crucial role in coordinating neutrophil migration to the insult site. Chemokines' recruitment activity is regulated by monomer- dimer equilibrium and binding to glycosaminoglycans (GAGs). GAG chains exist as covalently linked to core proteins of proteoglycans (PGs) and also as free chains due to cleavage by heparanases during the inflammatory response. Compared with free GAGs, binding to GAGs in a PG is influenced by their fixed directionality due to covalent linkage and restricted mobility. GAG interactions impact chemokine monomer/dimer levels, chemotactic and haptotactic gradients, life time, and presentation for receptor binding. Here, we show that Cxcl1 and Cxcl2 also form heterodimers. Using a disulfide-trapped Cxcl1-Cxcl2 heterodimer, we characterized its binding to free heparin using nuclear magnetic resonance and isothermal titration calorimetry, and to immobilized heparin and heparan sulfate using surface plasmon resonance. These data, in conjunction with molecular docking, indicate that the binding characteristics such as geometry and stoichiometry of the heterodimer are different between free and immobilized GAGs and are also distinctly different from those of the homodimers. We propose that the intrinsic asymmetry of the heterodimer structure, along with differences in its binding to PG GAGs and free GAGs, regulate chemokine function.
AB - Chemokines Cxcl1/KC and Cxcl2/MIP2 play a crucial role in coordinating neutrophil migration to the insult site. Chemokines' recruitment activity is regulated by monomer- dimer equilibrium and binding to glycosaminoglycans (GAGs). GAG chains exist as covalently linked to core proteins of proteoglycans (PGs) and also as free chains due to cleavage by heparanases during the inflammatory response. Compared with free GAGs, binding to GAGs in a PG is influenced by their fixed directionality due to covalent linkage and restricted mobility. GAG interactions impact chemokine monomer/dimer levels, chemotactic and haptotactic gradients, life time, and presentation for receptor binding. Here, we show that Cxcl1 and Cxcl2 also form heterodimers. Using a disulfide-trapped Cxcl1-Cxcl2 heterodimer, we characterized its binding to free heparin using nuclear magnetic resonance and isothermal titration calorimetry, and to immobilized heparin and heparan sulfate using surface plasmon resonance. These data, in conjunction with molecular docking, indicate that the binding characteristics such as geometry and stoichiometry of the heterodimer are different between free and immobilized GAGs and are also distinctly different from those of the homodimers. We propose that the intrinsic asymmetry of the heterodimer structure, along with differences in its binding to PG GAGs and free GAGs, regulate chemokine function.
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U2 - 10.1042/BCJ20200927
DO - 10.1042/BCJ20200927
M3 - Article
C2 - 33463672
AN - SCOPUS:85102110361
SN - 0264-6021
VL - 478
SP - 1009
EP - 1021
JO - Biochemical Journal
JF - Biochemical Journal
IS - 5
ER -