Structure of human cytomegalovirus UL144, an HVEM orthologue, bound to the B and T cell lymphocyte attenuator
Structure of human cytomegalovirus UL144, an HVEM orthologue, bound to the B and T cell lymphocyte attenuator
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DOI：
10.1074/jbc.ra119.009199
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发表时间：
2019-07-05
影响因子：
4.8
通讯作者：
Zajonc, Dirk M.
中科院分区：
文献类型：
--
作者：
Bitra, Aruna;Nemcovicova, Ivana;Zajonc, Dirk M.
人类巨细胞病毒（HCMV）是一种与宿主免疫系统共同进化以建立终身持久性的乙型疱疹病毒。HCMV编码许多免疫调节分子，包括糖蛋白UL144。UL144是肿瘤坏死因子受体超家族成员HVEM（疱疹病毒进入介质）的结构模拟物，可结合各种配体LIGHT、LT α、BTLA、CD160和gD。然而，与HVEM相反，UL144仅结合BTLA，抑制t细胞活化。在这里，我们报道了UL144-BTLA复合物的晶体结构，揭示了UL144利用其n端富含半胱氨酸结构域1 （CRD1）的残基独特地与BTLA相互作用。UL144较短的CRD2环也改变了BTLA与两个n端CRDs结合的相对方向。通过结构导向诱变，我们发现了BTLA突变体（L123A），该突变体干扰HVEM结合，但保留UL144相互作用。此外，我们的研究结果阐明了UL144和HVEM之间的结构差异，这解释了它的结合选择性，并强调它是设计优质免疫抑制性BTLA激动剂的合适支架。
Human cytomegalovirus (HCMV) is a beta-herpesvirus that has co-evolved with the host immune system to establish lifelong persistence. HCMV encodes many immunomodulatory molecules, including the glycoprotein UL144. UL144 is a structural mimic of the tumor necrosis factor receptor superfamily member HVEM (herpesvirus entry mediator), which binds to the various ligands LIGHT, LT alpha, BTLA, CD160, and gD. However, in contrast to HVEM, UL144 only binds BTLA, inhibiting T-cell activation. Here, we report the crystal structure of the UL144-BTLA complex, revealing that UL144 utilizes residues from its N-terminal cysteine-rich domain 1 (CRD1) to interact uniquely with BTLA. The shorter CRD2 loop of UL144 also alters the relative orientation of BTLA binding with both N-terminal CRDs. By employing structure-guided mutagenesis, we have identified a mutant of BTLA (L123A) that interferes with HVEM binding but preserves UL144 interactions. Furthermore, our results illuminate structural differences between UL144 and HVEM that explain its binding selectivity and highlight it as a suitable scaffold for designing superior, immune inhibitory BTLA agonists.