Structural basis of higher order oligomerization of KSHV inhibitor of cGAS.
Structural basis of higher order oligomerization of KSHV inhibitor of cGAS.
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DOI：
10.1073/pnas.2200285119
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发表时间：
2022-08-16
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
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卡波济肉瘤相关疱疹病毒（KSHV）环状GMP-AMP合酶（cGAS）抑制剂（KicGAS）是KSHV的主要被膜蛋白，对于逃避宿主免疫应答至关重要。KicGAS自组装功能，但组装的结构基础是未知的。在这里，我们提出了KicGAS的晶体结构，形成更高阶的组装。该结构揭示了KicGAS的寡聚化如何介导与cGAS抑制所需的DNA的多价相互作用。与同源蛋白质结构的比较揭示了不同的寡聚化特征，除了保守的功能，突出了在病毒进化的分歧。卡波济肉瘤相关疱疹病毒（KSHV）环状GMP-AMP合酶（cGAS）抑制剂（KicGAS）由ORF 52编码，是KSHV的保守的主要被膜蛋白，并且是第一个报道的cGAS的病毒抑制剂。在我们之前的研究中，我们发现KicGAS在溶液中高度寡聚化，并且寡聚化是其协同DNA结合以及抑制DNA诱导的相分离和cGAS活化所必需的。然而，KicGAS如何寡聚仍不清楚。在这里，我们以2.5 μ m的分辨率展示了KicGAS的晶体结构，它揭示了一个“L”形分子，L的每个臂基本上由单个α螺旋（α1和α2）形成。来自两个KicGAS分子的α2螺旋的反平行二聚化导致独特的“Z”形二聚体。令人惊讶的是，α1也是一个二聚化结构域。它与相邻二聚体的α1形成平行的二聚体亮氨酸拉链，导致形成KicGAS二聚体的无限链。参与亮氨酸拉链二聚体形成的残基是γ疱疹病毒ORF 52同源物中最保守的残基之一。自寡聚化增加了与DNA相互作用的价态和协同性。所得的多价相互作用对于与DNA形成液体冷凝物以及随后DNA被cGAS感测的隔离是至关重要的，这解释了其在限制cGAS活化中的作用。这里提出的结构不仅提供了对KicGAS功能的机制理解，而且为合理设计抗KSHV和相关病毒的抗病毒药物提供了分子靶标。
Kaposi's sarcoma–associated herpesvirus (KSHV) inhibitor of cyclic GMP–AMP synthase (cGAS) (KicGAS) is a major tegument protein of KSHV and crucial for the evasion of host immune responses. KicGAS self-assembles to function, yet the structural basis of assembly was unknown. Here, we present the crystal structure of KicGAS forming a higher order assembly. The structure reveals how oligomerization of KicGAS mediates multivalent interaction with DNA required for cGAS inhibition. Comparison with homologous protein structures reveals diverse oligomerization characteristics in addition to conserved features, highlighting divergence in virus evolution. Kaposi's sarcoma–associated herpesvirus (KSHV) inhibitor of cyclic GMP–AMP synthase (cGAS) (KicGAS) encoded by ORF52 is a conserved major tegument protein of KSHV and the first reported viral inhibitor of cGAS. In our previous study, we found that KicGAS is highly oligomerized in solution and that oligomerization is required for its cooperative DNA binding and for inhibiting DNA-induced phase separation and activation of cGAS. However, how KicGAS oligomerizes remained unclear. Here, we present the crystal structure of KicGAS at 2.5 Å resolution, which reveals an “L”-shaped molecule with each arm of the L essentially formed by a single α helix (α1 and α2). Antiparallel dimerization of α2 helices from two KicGAS molecules leads to a unique “Z”-shaped dimer. Surprisingly, α1 is also a dimerization domain. It forms a parallel dimeric leucine zipper with the α1 from a neighboring dimer, leading to the formation of an infinite chain of KicGAS dimers. Residues involved in leucine zipper dimer formation are among the most conserved residues across ORF52 homologs of gammaherpesviruses. The self-oligomerization increases the valence and cooperativity of interaction with DNA. The resultant multivalent interaction is critical for the formation of liquid condensates with DNA and consequent sequestration of DNA from being sensed by cGAS, explaining its role in restricting cGAS activation. The structure presented here not only provides a mechanistic understanding of the function of KicGAS but also informs a molecular target for rational design of antivirals against KSHV and related viruses.
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影响因子：
4.8
作者：
Benach, Jordi;Wang, Lili;Tong, Liang
通讯作者：
Tong, Liang
影响因子：
5.4
作者：
Kotsakis, A;Pomeranz, LE;Blaho, JA
通讯作者：
Blaho, JA
DOI：
10.1107/s2059798319011471
发表时间：
2019-10-01
影响因子：
2.2
作者：
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通讯作者：
Adams, Paul D.
影响因子：
64.8
作者：
Andreeva, Liudmila;Hiller, Bjoern;Hopfner, Karl-Peter
通讯作者：
Hopfner, Karl-Peter
影响因子：
5.4
作者：
Loftus MS;Verville N;Kedes DH
通讯作者：
Kedes DH