Effect of zinc on human IgG1 and its Fc纬R interactions

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• 作者：Sophie Sibé ; ril^a ; ^b ; ^c ; ^d ; ¹ ; René ; e Mé ; nez^e ; ¹ ; Sylvie Jorieux^d ; Christophe de Romeuf^d ; Dominique Bourel^d ; Wolf-Herman Fridman^a ; ^b ; ^c ; Fré ; dé ; ric Ducancel^f ; Enrico A. Stura^e ; ¹ ; Jean-Luc Teillaud^a ; ^b ; ^c ; ¹ ; ^{jean-luc.teillaud@crc.jussieu.fr} ; ^{jean-luc.teillaud@u255.bhdc.jussieu.fr}
• 关键词：CH2 domain ; CH3 domain ; Fc fragment ; Fc gamma receptor ; Histidine ; Zinc
• 刊名：Immunology Letters
• 出版年：2012
• 期刊代码：115_01652478
• 类别：med
• 出版时间：30 March, 2012
• 卷：143
• 期：1
• 页码：60-69
• 文件大小：1987 K

摘要

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 Fc纬R 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/Fc纬R interactions. The results of binding studies performed in the presence of EDTA on Fc纬R 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 Fc纬 receptors and their functions. Interaction with the inhibitory Fc纬RIIB is strongly perturbed by the mutations and mutant IgG1 H/K only weakly engages this receptor. By contrast, higher affinity Fc纬R are mostly unaffected.