Biophysical insight into protein-protein interactions in the Interleukin-11/Interleukin-11Rα/glycoprotein 130 signaling complex

Chinatsu Mori; Satoru Nagatoishi; Ryo Matsunaga; Daisuke Kuroda; Makoto Nakakido; Kouhei Tsumoto

doi:10.1016/j.bbrc.2023.10.010

Biophysical insight into protein-protein interactions in the Interleukin-11/Interleukin-11Rα/glycoprotein 130 signaling complex

Biochem Biophys Res Commun. 2023 Nov 19:682:174-179. doi: 10.1016/j.bbrc.2023.10.010. Epub 2023 Oct 4.

Authors

Chinatsu Mori¹, Satoru Nagatoishi², Ryo Matsunaga³, Daisuke Kuroda⁴, Makoto Nakakido³, Kouhei Tsumoto⁵

Affiliations

¹ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
² Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. Electronic address: s-nagatoishi@g.ecc.u-tokyo.ac.jp.
³ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁴ Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
⁵ Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Department of Bioengineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. Electronic address: tsumoto@bioeng.t.u-tokyo.ac.jp.

PMID: 37820452
DOI: 10.1016/j.bbrc.2023.10.010

Abstract

Interleukin-11 (IL-11) is a member of the interleukin-6 (IL-6) family of cytokines. IL-11 is a regulator of multiple events in hematopoiesis, and IL-11-mediated signaling is implicated in inflammatory disease, cancer, and fibrosis. All IL-6 family cytokines signal through the signal-transducing receptor, glycoprotein 130 (gp130), but these cytokines have distinct as well as overlapping biological functions. To understand IL-11 signaling at the molecular level, we performed a comprehensive interaction analysis of the IL-11 signaling complex, comparing it with the IL-6 complex, one of the best-characterized cytokine complexes. Our thermodynamic analysis revealed a clear difference between IL-11 and IL-6. Surface plasmon resonance analysis showed that the interaction between IL-11 and IL-11 receptor α (IL-11Rα) is entropy driven, whereas that between IL-6 and IL-6 receptor α (IL-6Rα) is enthalpy driven. Our analysis using isothermal titration calorimetry revealed that the binding of gp130 to the IL-11/IL-11Rα complex results in entropy loss, but that the interaction of gp130 with the IL-6/IL-6Rα complex results in entropy gain. Our hydrogen-deuterium exchange mass spectrometry experiments suggested that the D2 domain of gp130 was not involved in IL-6-like interactions in the IL-11/IL-11Rα complex. It has been reported that IL-6 interaction with gp130 in the signaling complex was characterized through the hydrophobic interface located in its D2 domain of gp130. Our findings suggest that unique interactions of the IL-11 signaling complex with gp130 are responsible for the distinct biological activities of IL-11 compared to IL-6.

Keywords: Glycoprotein 130; Interleukin-11; Interleukin-6; Signaling complex.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytokine Receptor gp130 / metabolism
Cytokines
Glycoproteins
Interleukin-11*
Interleukin-6* / metabolism
Receptors, Interleukin-6 / metabolism

Substances

Interleukin-11
Cytokine Receptor gp130
Interleukin-6
Receptors, Interleukin-6
Cytokines
Glycoproteins