Wines Bruce D, Trist Halina M, Ramsland Paul A, Hogarth P Mark
Helen Macpherson Smith Trust Inflammatory Disease Laboratory, The Macfarlane Burnet Institute for Medical Research and Public Health, Austin Health Campus, Heidelberg, Victoria 3084, Australia.
Helen Macpherson Smith Trust Inflammatory Disease Laboratory, The Macfarlane Burnet Institute for Medical Research and Public Health, Austin Health Campus, Heidelberg, Victoria 3084, Australia.
J Biol Chem. 2006 Jun 23;281(25):17108-17113. doi: 10.1074/jbc.M601640200. Epub 2006 Apr 19.
The transmembrane (TM) region of the Fc receptor-gamma (FcRgamma) chain is responsible for the association of this ubiquitous signal transduction subunit with many immunoreceptor ligand binding chains, making FcRgamma key to a number of leukocyte activities in immunity and disease. Some receptors contain a TM arginine residue that interacts with Asp-11 of the FcRgamma subunit, but otherwise the molecular basis for the FcRgamma subunit interactions is largely unknown. This study reports residues in the TM region of the FcRgamma subunit are important for association with the high affinity IgE receptor FcepsilonRI and a leukocyte receptor cluster member, the IgA receptor FcalphaRI. FcRgamma residue Leu-21 was essential for surface expression of FcepsilonRIalpha/gamma2 and Tyr-8, Leu-14, and Phe-15 contributed to expression. Likewise, detergent-stable FcRgamma association with FcalphaRI was also dependent on Leu-14 and Leu-21 and in addition required residues Tyr-17, Tyr-25, and Cys-26. Modeling the TM regions of the FcRgamma dimer indicated these residues interacting with both FcalphaRI and FcepsilonRI are near the interface between the two FcRgamma TM helices. Furthermore, the FcRgamma residues interacting with FcalphaRI form a leucine zipper-like interface with mutagenesis confirming a complementary interface comprising FcalphaRI residues Leu-217, Leu-220, and Leu-224. The dependence of these two nonhomologous receptor interactions on FcRgamma Leu-14 and Leu-21 suggests that all the associated Fc receptors and the activating leukocyte receptor cluster members interact with this one site. Taken together these data provide a molecular basis for understanding how disparate receptor families assemble with the FcRgamma subunit.
Fc受体γ（FcRγ）链的跨膜（TM）区域负责将这个普遍存在的信号转导亚基与许多免疫受体配体结合链进行关联，使得FcRγ成为免疫和疾病中许多白细胞活动的关键因素。一些受体含有一个与FcRγ亚基的Asp-11相互作用的TM精氨酸残基，但除此之外，FcRγ亚基相互作用的分子基础在很大程度上尚不清楚。本研究报告称，FcRγ亚基TM区域中的残基对于与高亲和力IgE受体FcepsilonRI以及白细胞受体簇成员IgA受体FcalphaRI的关联很重要。FcRγ残基Leu-21对于FcepsilonRIalpha/gamma2的表面表达至关重要，而Tyr-8、Leu-14和Phe-15有助于其表达。同样，与FcalphaRI的去污剂稳定型FcRγ关联也依赖于Leu-14和Leu-21，此外还需要残基Tyr-17、Tyr-25和Cys-26。对FcRγ二聚体的TM区域进行建模表明，这些与FcalphaRI和FcepsilonRI都相互作用的残基靠近两个FcRγ TM螺旋之间的界面。此外，与FcalphaRI相互作用的FcRγ残基形成了一个亮氨酸拉链样界面，诱变证实了一个由FcalphaRI残基Leu-217、Leu-220和Leu-224组成的互补界面。这两种非同源受体相互作用对FcRγ Leu-14和Leu-21的依赖性表明，所有相关的Fc受体和激活的白细胞受体簇成员都与这一个位点相互作用。这些数据综合起来为理解不同的受体家族如何与FcRγ亚基组装提供了分子基础。
