TU Darmstadt / ULB / TUbiblio

Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232.

Xu, Liling and Xia, Mengdie and Guo, Jun and Sun, Xiaolin and Li, Hua and Xu, Chenguang and Gu, Xiaomei and Zhang, Haowen and Yi, Junyang and Fang, Yan and Xie, Hengyi and Wang, Jing and Shen, Zhixun and Xue, Boxin and Sun, Yujie and Meckel, Tobias and Chen, Ying-Hua and Hu, Zhibin and Li, Zhanguo and Xu, Chenqi and Gong, Haipeng and Liu, Wanli (2016):
Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232.
In: The Journal of experimental medicine, pp. 2707-2727, 213, (12), ISSN 1540-9538,
[Article]

Abstract

FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of FcγRIIB-T232 at both functional and structural levels. Our results showed that FcγRIIB-T232 exhibited significantly reduced lateral mobility compared with FcγRIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for FcγRIIB-T232 to diffuse and interact with the ICs, FcγRIIB-T232 can restore its inhibitory function. Moreover, substituting the FcγRIIB-T232 TM domain with that of a fast floating CD86 molecule restored both the rapid mobility and the inhibitory function, which further corroborated the importance of fast mobility for FcγRIIB to function. Mechanistically, the crippled lateral mobility of FcγRIIB-T232 can be explained by the structural changes of the TM domain. Both atomistic simulations and nuclear magnetic resonance measurement indicated that the TM helix of FcγRIIB-T232 exhibited a more inclined orientation than that of FcγRIIB-I232, thus resulting in a longer region embedded in the membrane. Therefore, we conclude that the single-residue polymorphism T232 enforces the inclination of the TM domain and thereby reduces the lateral mobility and inhibitory functions of FcγRIIB.

Item Type: Article
Erschienen: 2016
Creators: Xu, Liling and Xia, Mengdie and Guo, Jun and Sun, Xiaolin and Li, Hua and Xu, Chenguang and Gu, Xiaomei and Zhang, Haowen and Yi, Junyang and Fang, Yan and Xie, Hengyi and Wang, Jing and Shen, Zhixun and Xue, Boxin and Sun, Yujie and Meckel, Tobias and Chen, Ying-Hua and Hu, Zhibin and Li, Zhanguo and Xu, Chenqi and Gong, Haipeng and Liu, Wanli
Title: Impairment on the lateral mobility induced by structural changes underlies the functional deficiency of the lupus-associated polymorphism FcγRIIB-T232.
Language: English
Abstract:

FcγRIIB functions to suppress the activation of immune cells. A single-nucleotide polymorphism in the transmembrane (TM) domain of FcγRIIB, FcγRIIB-T232, is associated with lupus. In this study, we investigated the pathogenic mechanism of FcγRIIB-T232 at both functional and structural levels. Our results showed that FcγRIIB-T232 exhibited significantly reduced lateral mobility compared with FcγRIIB-I232 and was significantly less enriched into the microclusters of immune complexes (ICs) after stimulation. However, if sufficient responding time is given for FcγRIIB-T232 to diffuse and interact with the ICs, FcγRIIB-T232 can restore its inhibitory function. Moreover, substituting the FcγRIIB-T232 TM domain with that of a fast floating CD86 molecule restored both the rapid mobility and the inhibitory function, which further corroborated the importance of fast mobility for FcγRIIB to function. Mechanistically, the crippled lateral mobility of FcγRIIB-T232 can be explained by the structural changes of the TM domain. Both atomistic simulations and nuclear magnetic resonance measurement indicated that the TM helix of FcγRIIB-T232 exhibited a more inclined orientation than that of FcγRIIB-I232, thus resulting in a longer region embedded in the membrane. Therefore, we conclude that the single-residue polymorphism T232 enforces the inclination of the TM domain and thereby reduces the lateral mobility and inhibitory functions of FcγRIIB.

Journal or Publication Title: The Journal of experimental medicine
Volume: 213
Number: 12
Divisions: 10 Department of Biology
10 Department of Biology > Membrane Dynamics
Date Deposited: 13 Feb 2017 11:57
Identification Number: pmid:27799621
Export:
Suche nach Titel in: TUfind oder in Google

Optionen (nur für Redakteure)

View Item View Item