Abstract
The three-dimensional structure of a human IgG1 Fc fragment bound to wild-type human FcγRI is reported. The structure of the corresponding complex was solved at a resolution of 2.4 Å using molecular replacement; this is the highest resolution achieved for an unmutated FcγRI molecule. This study highlights the critical structural and functional role played by the second extracellular subdomain of FcγRI. It also explains the long-known major energetic contribution of the Fc `LLGG' motif at positions 234-237, and particularly of Leu235, via a `lock-and-key' mechanism. Finally, a previously held belief is corrected and a differing view is offered on the recently proposed direct role of Fc carbohydrates in the corresponding interaction. Structural evidence is provided that such glycan-related effects are strictly indirect.
Highlights
The family of IgG Fc gamma receptors (Fc Rs) play a crucial role in controlling the immune response in mammals (Nimmerjahn & Ravetch, 2006, 2008; Guilliams et al, 2014)
We carried out a crystallographic study of the complex formed between Fc RI extracellular domain (ECD) and the Fc portion of a human IgG1 in an effort to account for the high affinity of the corresponding interaction
The search model for Fc consisted of another Fc portion exhibiting the same amino-acid sequence as in this study, expressed and purified in the same conditions as described above and the structure of which had been determined at high resolution (1.5 A ; unpublished data)
Summary
The family of IgG Fc gamma receptors (Fc Rs) play a crucial role in controlling the immune response in mammals (Nimmerjahn & Ravetch, 2006, 2008; Guilliams et al, 2014). In humans, this family comprises a complex array of various members (Fc RI, Fc RII, Fc RIIIA and Fc RIIIB) and their allelic variants. This family comprises a complex array of various members (Fc RI, Fc RII, Fc RIIIA and Fc RIIIB) and their allelic variants These differ in their function (activating versus inhibitory), structural features and affinities for different IgG isotypes. While Lu et al (2015) reported that Fc RI recognizes Fc glycans and attributed the high affinity between the two partners to this structural feature, Kiyoshi et al (2015) found that such glycans make only little contribution to the interaction
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