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Reversal of some viral IL‐6 electrostatic properties compared to IL‐6 contributes to a loss of alpha receptor component recruitment
Author(s) -
Perret David,
Rousseau François,
Tran Vinh,
Gascan Hugues
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20445
Subject(s) - glycoprotein 130 , receptor , mediator , complex formation , chemistry , glycoprotein , microbiology and biotechnology , biology , signal transduction , biophysics , biochemistry , inorganic chemistry , stat3
Human interleukin‐6 (hIL‐6) is a pleiotropic mediator of activation and proliferation across a large number of different cell types. Human herpesvirus‐8 (HHV‐8) has been associated with classical and AIDS‐related Kaposi's sarcoma (KS). HHV‐8 encodes viral IL‐6 (vIL‐6), a functional homolog of human interleukin‐6, that promotes the growth of KS and of some lymphoma cells. Signaling induced by human IL‐6 requires recruitment of the glycoprotein gp130, which acts as the signal transducing chain, and of IL‐6Rα, which is necessary for cognate recognition and high affinity receptor complex formation. In contrast, the formation of a functional complex between vIL‐6 and gp130 does not require the presence of IL‐6Rα. The physico‐chemical properties of vIL‐6 have been analyzed and compared to those of hIL‐6 and of the receptor chains, gp130 and IL‐6Rα. Interaction sites on vIL‐6 involve more hydrophobic residues than those of hIL‐6. The electrostatic fields induced by vIL‐6 and IL‐6Rα are repulsive and prevent interaction between vIL‐6 and IL‐6Rα, whereas the electrostatic field induced by hIL‐6 steers the complex formation with IL‐6Rα. Subsequently, electrostatic binding free energy in the vIL‐6/IL‐6Rα complex is destabilizing, whereas it is stabilizing in the complex comprising hIL‐6. These properties result from charge reversals between viral and human IL‐6, an unusual phenomenon of amino acid substitutions within a homologous protein family. This suggests a selection pressure for vIL‐6 to by‐pass the IL‐6Rα control of host defense against virus infection. This selection pressure has yielded the reversal of electrostatic properties of vIL‐6 when compared to hIL‐6. Proteins 2005. © 2005 Wiley‐Liss, Inc.