Cross-Reactivity of the gpl30 IGD with Cytokine Site III

A/B loop of the cytokine, forming a sheet-Uke structure with the A/B loop (Fig. 6, top). In both the viral and human IL-6 site II complexes, the A/B loop is ordered, whereas this loop I disordered in most unUganded cytokines. In both the viral IL-6 and human IL-6 site II interfaces, a Trp residue (Trp and Trp respectively) forms the heart of the interfaces, burying more surface than any other residues (Fig. 6, Fig. 7A). The placement of this aromatic residue is a conserved feature of aU gplSO-cytokines and so likely represents the site III hotspot. This central Trp is surrounded by a chemically diverse array of amino acids to make up a very large interaction surface with the gplSO D1 domain. In fact, many of the contacts are main chain Van der Waals and hydrogen bonds with the 

LIF receptor also uses its Ig domain (D3) to receive site III epitopes of GNTF, LIF, GT-1, OSM, and others. So the Ig domain of LIF receptor is, in fact, more cross-reactive than gplSO. The site III structures of all gp 130-cytokines maintain a conserved aromatic residue at the tip of the D helix (Fig. 7) that is certainly the structural analog to the Trp residues we see in the center of the gplSO site III interface. Therefore we predict that the LIFR site III interface cross-reactivity is achieved by using similar structural features at the gplSO IgD. 

Predicting the Higher-Order Assemblies of the Asymmetric Complexes (gp130/LIFR) 

The authors acknowledge Mathias Rickert and the members of the Garcia lab for helpful discussions. The authors also acknowledge the NIH, the Keck Foundation, and the Cancer Research Institute for support. M.J.B. is supported by a Natural Sciences and Engineering Research Council of Canada post-doctoral fellowship. 

Aasland, D., Oppmann, B., Grotzinger, J., Rose-John, S., and Kallen, K. J. (2002). The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex. J. Mol. Biol. 315, 637-646. 

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Cross-Reactivity of the gpl30 IGD with Cytokine Site III. 132... 

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