TY - JOUR
T1 - Molecular Mechanisms for Viral Mimicry of a Human Cytokine
T2 - Activation of gp130 by HHV-8 Interleukin-6
AU - Boulanger, Martin J.
AU - Chow, Dar Chone
AU - Brevnova, Elena
AU - Martick, Monika
AU - Sandford, Gordon
AU - Nicholas, John
AU - Garcia, K. Christopher
N1 - Funding Information:
This work was supported by NIH grant RO1-AI51321 and Pew Scholars, Cancer Research Institute, and Keck Foundation grants to K.C.G., and NIH R01-CA76445 to J.N. M.J.B. is supported by a National Science and Engineering Research Council (NSERC) of Canada post-doctoral fellowship.
PY - 2004/1/9
Y1 - 2004/1/9
N2 - Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (hIL-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific α-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "α-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human α-receptor (IL-6Rα) to form a hexameric vIL-6/IL-6Rα/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Rα, post facto, in a "vIL-6-dependent" fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart.
AB - Kaposi's sarcoma-associated herpesvirus (KSHV, or HHV-8) encodes a pathogenic viral homologue of human interleukin-6 (IL-6). In contrast to human IL-6 (hIL-6), viral IL-6 (vIL-6) binds directly to, and activates, the shared human cytokine signaling receptor gp130 without the requirement for pre-complexation to a specific α-receptor. Here, we dissect the biochemical and functional basis of vIL-6 mimicry of hIL-6. We find that, in addition to the "α-receptor-independent" tetrameric vIL-6/gp130 complex, the viral cytokine can engage the human α-receptor (IL-6Rα) to form a hexameric vIL-6/IL-6Rα/gp130 complex with enhanced signaling potency. In contrast to the assembly sequence of the hIL-6 hexamer, the preformed vIL-6/gp130 tetramer can be decorated with IL-6Rα, post facto, in a "vIL-6-dependent" fashion. A detailed comparison of the viral and human cytokine/gp130 interfaces indicates that vIL-6 has evolved a unique molecular strategy to interact with gp130, as revealed by an almost entirely divergent structural makeup of its receptor binding sites. Viral IL-6 appears to utilize an elegant combination of both convergent, and unexpectedly divergent, molecular strategies to oligomerize gp130 and activate similar downstream signaling cascades as its human counterpart.
KW - KSHV/HHV-8
KW - Molecular mimicry
KW - Protein-protein interactions
KW - Viral pathogenesis
KW - gp130
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U2 - 10.1016/j.jmb.2003.10.070
DO - 10.1016/j.jmb.2003.10.070
M3 - Article
C2 - 14672670
AN - SCOPUS:0345735665
SN - 0022-2836
VL - 335
SP - 641
EP - 654
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 2
ER -