The localisation of the heparin binding sites of human and murine interleukin-12 within the carboxyterminal domain of the P40 subunit

Cytokine
Pascale GarnierC C Rider

Abstract

We have previously shown that the heterodimeric cytokine interleukin-12, and the homodimer of its larger subunit p40, both bind to heparin and heparan sulfate with relatively high affinity. In the present study we characterised these interactions using a series of chemically modified heparins as competitive inhibitors. Human interleukin-12 and p40 homodimer show indistinguishable binding profiles with a panel of heparin derivatives, but that of murine interleukin-12 is distinct. Heparin markedly protects the human and murine p40 subunits, but not the p35 subunits, from cleavage by the bacterial endoprotease LysC, further implicating the larger subunit as the location of the heparin binding site. Moreover the essential role of the carboxyterminal D3 domain in heparin binding is established by the failure of a truncated construct of the p40 subunit lacking this domain to bind. Predictive docking calculations indicate that a cluster of basic residues at the tip of the exposed C'D' loop within D3 is important in heparin binding. However since the human and murine C'D' loops differ considerably in length, the mode and three dimensional orientation of heparin binding are likely to differ substantially between the human and murine p40...Continue Reading

Citations

Jan 24, 2019·The Journal of Biological Chemistry·Khue G NguyenDavid A Zaharoff
Aug 23, 2020·Journal of Clinical Medicine·Gustavo R RossiFernando Souza-Fonseca-Guimaraes
Oct 20, 2019·Journal of Controlled Release : Official Journal of the Controlled Release Society·Daniel HachimMolly M Stevens

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