Effect of zinc on human IgG1 and its FcγR interactions
- PMID: 22553781
- DOI: 10.1016/j.imlet.2012.02.002
Effect of zinc on human IgG1 and its FcγR interactions
Abstract
In the present study, we show that histidines 310 and 435 at the CH2-CH3 interface of the Fc portion of human IgG1 can coordinate a Zn2+ and participate in the control of the CH2-CH2 interdomain opening. Structures obtained in the absence of Zn2+ have a reduced interdomain gap that likely hamper FcγR binding. This closed conformation of the Fc is stabilized by inter-CH2 domain sugar contacts. Zinc appears to counteract the sugar mediated constriction, suggesting that zinc could be an important control factor in IgG1/FcγR interactions. The results of binding studies performed in the presence of EDTA on FcγR expressing cells supports this hypothesis. When a mutated Fc fragment, in which histidines 310 and 435 have been substituted by lysines (Fc H/K), was compared with the wild-type Fc in crystallographic studies, we found that the mutations leave the interface unaltered but have a long-range effect on the CH2 interdomain separation. Moreover, these substitutions have a differential effect on the binding of IgG1 to Fcγ receptors and their functions. Interaction with the inhibitory FcγRIIB is strongly perturbed by the mutations and mutant IgG1 H/K only weakly engages this receptor. By contrast, higher affinity FcγR are mostly unaffected.
Similar articles
-
Structural analysis of Fc/FcγR complexes: a blueprint for antibody design.Immunol Rev. 2015 Nov;268(1):201-21. doi: 10.1111/imr.12365. Immunol Rev. 2015. PMID: 26497522 Review.
-
Fcγ receptor pathways during active and passive immunization.Immunol Rev. 2015 Nov;268(1):88-103. doi: 10.1111/imr.12343. Immunol Rev. 2015. PMID: 26497515 Free PMC article. Review.
-
Restricted motion of the conserved immunoglobulin G1 N-glycan is essential for efficient FcγRIIIa binding.Structure. 2014 Oct 7;22(10):1478-88. doi: 10.1016/j.str.2014.08.002. Epub 2014 Sep 4. Structure. 2014. PMID: 25199692 Free PMC article.
-
IgG2 Fc structure and the dynamic features of the IgG CH2-CH3 interface.Mol Immunol. 2013 Nov;56(1-2):131-9. doi: 10.1016/j.molimm.2013.03.018. Epub 2013 Apr 28. Mol Immunol. 2013. PMID: 23628091
-
The IgG Fc contains distinct Fc receptor (FcR) binding sites: the leukocyte receptors Fc gamma RI and Fc gamma RIIa bind to a region in the Fc distinct from that recognized by neonatal FcR and protein A.J Immunol. 2000 May 15;164(10):5313-8. doi: 10.4049/jimmunol.164.10.5313. J Immunol. 2000. PMID: 10799893
Cited by
-
Metal Ion Interactions with mAbs: Part 2. Zinc-Mediated Aggregation of IgG1 Monoclonal Antibodies.Pharm Res. 2021 Aug;38(8):1387-1395. doi: 10.1007/s11095-021-03089-7. Epub 2021 Aug 11. Pharm Res. 2021. PMID: 34382142
-
Crystal Structures of PF-06438179/GP1111, an Infliximab Biosimilar.BioDrugs. 2020 Feb;34(1):77-87. doi: 10.1007/s40259-019-00390-1. BioDrugs. 2020. PMID: 31650490 Free PMC article.
-
CH2 domain orientation of human immunoglobulin G in solution: Structural comparison of glycosylated and aglycosylated Fc regions using small-angle X-ray scattering.MAbs. 2019 Apr;11(3):453-462. doi: 10.1080/19420862.2018.1546086. Epub 2018 Dec 12. MAbs. 2019. PMID: 30513259 Free PMC article.
-
A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1.J Biol Chem. 2017 Sep 1;292(35):14706-14717. doi: 10.1074/jbc.M117.793497. Epub 2017 Jun 27. J Biol Chem. 2017. PMID: 28655766 Free PMC article.
-
A Novel Platform for the Potentiation of Therapeutic Antibodies Based on Antigen-Dependent Formation of IgG Hexamers at the Cell Surface.PLoS Biol. 2016 Jan 6;14(1):e1002344. doi: 10.1371/journal.pbio.1002344. eCollection 2016 Jan. PLoS Biol. 2016. PMID: 26736041 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous