Reversal of some viral IL-6 electrostatic properties compared to IL-6 contributes to a loss of alpha receptor component recruitment.
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-6Ralpha, 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-6Ralpha. 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-6Ralpha. Interaction sites on vIL-6 involve more hydrophobic residues than those of hIL-6. The electrostatic fields induced by vIL-6 and IL-6Ralpha are repulsive and prevent interaction between vIL-6 and IL-6Ralpha, whereas the electrostatic field induced by hIL-6 steers the complex formation with IL-6Ralpha. Subsequently, electrostatic binding free energy in the vIL-6/IL-6Ralpha 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-6Ralpha 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.
Perret
David
D
INSERM U564, CHU d'Angers, Angers, France.
Rousseau
François
F
Tran
Vinh
V
Gascan
Hugues
H
D000595:Amino Acid Sequence; D039301:Computers, Molecular; D050822:Cytokine Receptor gp130 / Q000737:chemistry / Q000378:metabolism; D019143:Evolution, Molecular; D019288:Herpesvirus 8, Human / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015850:Interleukin-6 / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014764:Viral Proteins; D050822:Cytokine Receptor gp130