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

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.

SUBMITTER: Xu L

PROVIDER: S-EPMC5110019 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Xu Liling L Xia Mengdie M Guo Jun J Sun Xiaolin X Li Hua H Xu Chenguang C Gu Xiaomei X Zhang Haowen H Yi Junyang J Fang Yan Y Xie Hengyi H Wang Jing J Shen Zhixun Z Xue Boxin B Sun Yujie Y Meckel Tobias T Chen Ying-Hua YH Hu Zhibin Z Li Zhanguo Z Xu Chenqi C Gong Haipeng H Liu Wanli W

The Journal of experimental medicine 20161031 12

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 st ...[more]

PMID: 27799621

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

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

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