Allosteric regulation of binding specificity of HVEM for CD160 and BTLA ligands upon G89F mutation.
Allosteric regulation of binding specificity of HVEM for CD160 and BTLA ligands upon G89F mutation.
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DOI：
10.1016/j.crstbi.2021.11.001
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发表时间：
2021
影响因子：
2.8
通讯作者：
Fiser A
中科院分区：
文献类型：
--
作者：
Shrestha R;Garrett-Thomson S;Liu W;Almo SC;Fiser A
由疱疹病毒进入介体（HVEM）与TNF和IG超家族成员的接合介导的分子相互作用在调节炎症和抑制反应的T细胞活化途径中产生不同的信号。HVEM与CD160和B和T淋巴细胞衰减因子（BTLA）相互作用，两者均为免疫球蛋白（IG）超家族的成员，它们具有与LIGHT（一种TNF配体）独特的共同结合位点。BTLA或CD160与HVEM的接合以环境依赖性方式向宿主免疫应答递送抑制或刺激信号，而HVEM与LIGHT的接合导致促炎应答。我们鉴定了人HVEM中的突变G89F，其直接干扰人LIGHT相互作用，但有趣的是，还通过涉及远离突变位点的识别表面的明显变构机制差异性地调节人BTLA和CD 160的结合。具体而言，在基于细胞的测定中，G89F突变增强了CD160的结合，同时降低了BTLA与HVEM的结合。野生型和G89F突变HVEM，绑定到不同的配体集的分子动力学模拟，进行定义这种意想不到的变构效应的分子基础。利用这些结果来设计具有改变的结合特异性的另外的人HVEM突变体。HVEM G89F突变变构增加CD160并降低BTLA结合。分子动力学模拟揭示了变构调节的分子机制。CRD 1结构域的相对位移引起结合界面的变化。当LIGHT配体结合时，进一步强调变构效应。设计了新的突变体，其恢复了基于细胞的论文中的选择性结合。
Molecular interactions mediated by engagement of the Herpes virus entry mediator (HVEM) with members of TNF and Ig superfamily generate distinct signals in T cell activation pathways that modulate inflammatory and inhibitory responses. HVEM interacts with CD160 and B and T lymphocyte attenuator (BTLA), both members of the immunoglobulin (Ig) superfamily, which share a common binding site that is unique from that of LIGHT, a TNF ligand. BTLA or CD160 engagement with HVEM deliver inhibitory or stimulatory signals to the host immune response in a context dependent fashion, whereas HVEM engagement with LIGHT results in pro-inflammatory responses. We identified a mutation in human HVEM, G89F, which directly interferes with the human LIGHT interaction, but interestingly, also differentially modulates the binding of human BTLA and CD160 via an apparent allosteric mechanism involving recognition surfaces remote from the site of the mutation. Specifically, the G89F mutation enhances binding of CD160, while decreasing that of BTLA to HVEM in cell-based assays. Molecular dynamics simulations for wild-type and G89F mutant HVEM, bound to different sets of ligands, were performed to define the molecular basis of this unexpected allosteric effect. These results were leveraged to design additional human HVEM mutants with altered binding specificities. HVEM G89F mutation allosterically increases CD160 and decreases BTLA binding. MD simulations revealed the molecular mechanism of allosteric regulation. A relative shift of CRD1 domain induces a change of the binding interface. When LIGHT ligand is bound the allosteric effect is further emphasized. New mutants were designed that reverted the selective binding in cell based essays.
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DOI：
10.1002/prot.340110305
发表时间：
1991-01-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
ICHIYE, T;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
淋巴瘤中HVEM肿瘤抑制剂的丧失和修饰的CAR-T细胞恢复。
影响因子：
64.5
作者：
Boice M;Salloum D;Mourcin F;Sanghvi V;Amin R;Oricchio E;Jiang M;Mottok A;Denis-Lagache N;Ciriello G;Tam W;Teruya-Feldstein J;de Stanchina E;Chan WC;Malek SN;Ennishi D;Brentjens RJ;Gascoyne RD;Cogné M;Tarte K;Wendel HG
通讯作者：
Wendel HG
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
4.4
作者：
Bussi, Giovanni;Donadio, Davide;Parrinello, Michele
通讯作者：
Parrinello, Michele