SH2域
变构调节
免疫受体酪氨酸激活基序
锡克
磷酸化
蛋白激酶结构域
细胞生物学
汉普地区
信号转导
酪氨酸激酶
T细胞受体
化学
生物化学
结合位点
生物物理学
生物
绑定域
受体
T细胞
遗传学
基因
免疫系统
突变体
作者
Kaustav Gangopadhyay,Bharat Manna,Swarnendu Roy,Sunitha R. Kumari,Olivia Debnath,Subhankar Chowdhury,Amit Ghosh,Rahul Das
摘要
T-cell receptor (TCR) signaling is initiated by recruiting ZAP-70 to the cytosolic part of TCR. ZAP-70, a non-receptor tyrosine kinase, is composed of an N-terminal tandem SH2 (tSH2) domain connected to the C-terminal kinase domain. The ZAP-70 is recruited to the membrane through binding of tSH2 domain and the doubly phosphorylated ITAM motifs of CD3 chains in the TCR complex. Our results show that the tSH2 domain undergoes a biphasic structural transition while binding to the doubly phosphorylated ITAM-ζ1 peptide. The C-terminal SH2 domain binds first to the phosphotyrosine residue of ITAM peptide to form an encounter complex leading to subsequent binding of second phosphotyrosine residue to the N-SH2 domain. We decipher a network of noncovalent interactions that allosterically couple the two SH2 domains during binding to doubly phosphorylated ITAMs. Mutation in the allosteric network residues, for example, W165C, uncouples the formation of encounter complex to the subsequent ITAM binding thus explaining the altered recruitment of ZAP-70 to the plasma membrane causing autoimmune arthritis in mice. The proposed mechanism of allosteric coupling is unique to ZAP-70, which is fundamentally different from Syk, a close homolog of ZAP-70 expressed in B-cells.
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