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结构显示，E3 连接酶 XIAP 的 BIR2 结构域结合在 RIPK2 激酶二聚体界面上。

Structure shows that the BIR2 domain of E3 ligase XIAP binds across the RIPK2 kinase dimer interface.

机构信息

https://ror.org/01zjc6908 European Molecular Biology Laboratory, Grenoble, France.

University Grenoble Alpes, IBS, Grenoble, France.

出版信息

Life Sci Alliance. 2023 Sep 6;6(11). doi: 10.26508/lsa.202201784. Print 2023 Nov.

DOI:10.26508/lsa.202201784
PMID:37673444
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10485824/
Abstract

RIPK2 is an essential adaptor for NOD signalling and its kinase domain is a drug target for NOD-related diseases, such as inflammatory bowel disease. However, recent work indicates that the phosphorylation activity of RIPK2 is dispensable for signalling and that inhibitors of both RIPK2 activity and RIPK2 ubiquitination prevent the essential interaction between RIPK2 and the BIR2 domain of XIAP, the key RIPK2 ubiquitin E3 ligase. Moreover, XIAP BIR2 antagonists also block this interaction. To reveal the molecular mechanisms involved, we combined native mass spectrometry, NMR, and cryo-electron microscopy to determine the structure of the RIPK2 kinase BIR2 domain complex and validated the interface with in cellulo assays. The structure shows that BIR2 binds across the RIPK2 kinase antiparallel dimer and provides an explanation for both inhibitory mechanisms. It also highlights why phosphorylation of the kinase activation loop is dispensable for signalling while revealing the structural role of RIPK2-K209 residue in the RIPK2-XIAP BIR2 interaction. Our results clarify the features of the RIPK2 conformation essential for its role as a scaffold protein for ubiquitination.

摘要

RIPK2 是 NOD 信号的重要衔接子，其激酶结构域是 NOD 相关疾病（如炎症性肠病）的药物靶点。然而，最近的研究表明，RIPK2 的磷酸化活性对于信号传递并非必需，RIPK2 活性和 RIPK2 泛素化的抑制剂均可防止 RIPK2 与 XIAP 的 BIR2 结构域之间的必需相互作用，XIAP 是 RIPK2 泛素 E3 连接酶的关键。此外，XIAP BIR2 拮抗剂也可阻断该相互作用。为了揭示所涉及的分子机制，我们结合了天然质谱、NMR 和冷冻电镜技术来确定 RIPK2 激酶 BIR2 结构域复合物的结构，并通过细胞内测定验证了该界面。该结构表明，BIR2 横跨 RIPK2 激酶的反平行二聚体结合，并为两种抑制机制提供了解释。它还突出了为什么激酶激活环的磷酸化对于信号传递并非必需，同时揭示了 RIPK2-K209 残基在 RIPK2-XIAP BIR2 相互作用中的结构作用。我们的结果阐明了 RIPK2 构象的特征，这些特征对于其作为泛素化支架蛋白的作用至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/691d/10485824/049b944b840b/LSA-2022-01784_FigS12.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/691d/10485824/049b944b840b/LSA-2022-01784_FigS12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/691d/10485824/44c80d8a6796/LSA-2022-01784_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/691d/10485824/a184eb6d6539/LSA-2022-01784_FigS1.jpg
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