Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-11-19 DOI:10.1016/j.str.2024.10.028

Anna Yudenko, Sergey Bukhdruker, Pavel Shishkin, Sergey Rodin, Anastasia Burtseva, Aleksandr Petrov, Natalia Pigareva, Alexey Sokolov, Egor Zinovev, Igor Eliseev, Alina Remeeva, Egor Marin, Alexey Mishin, Valentin Gordeliy, Ivan Gushchin, Aleksandr Ischenko, Valentin Borshchevskiy

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Abstract

Interleukin-6 (IL-6) is a multifaceted cytokine essential in many immune system processes and their regulation. It also plays a key role in hematopoiesis, and in triggering the acute phase reaction. IL-6 overproduction is critical in chronic inflammation associated with autoimmune diseases like rheumatoid arthritis and contributes to cytokine storms in COVID-19 patients. Over 20 years ago, researchers proposed that IL-6, which is typically monomeric, can also form dimers via a domain-swap mechanism, with indirect evidence supporting their existence. The physiological significance of IL-6 dimers was shown in B-cell chronic lymphocytic leukemia. However, no structures have been reported so far. Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.

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IL-6 结构域互换二聚体抑制信号复合体的结构基础

白细胞介素-6（IL-6）是一种多方面的细胞因子，对许多免疫系统过程及其调控至关重要。它在造血和引发急性期反应中也起着关键作用。IL-6 的过度分泌在与类风湿性关节炎等自身免疫性疾病相关的慢性炎症中至关重要，并导致 COVID-19 患者的细胞因子风暴。20 多年前，研究人员提出，IL-6 通常是单体，但也可以通过结构域交换机制形成二聚体，并有间接证据支持二聚体的存在。在 B 细胞慢性淋巴细胞白血病中显示了 IL-6 二聚体的生理意义。然而，迄今为止还没有关于其结构的报道。在这里，我们展示了计算方法无法预测的 IL-6 结构域互换二聚体的晶体结构。该结构解释了为什么 IL-6 二聚体在信号复合物形成过程中与 IL-6 单体具有拮抗作用，并为 IL-6 靶向疗法提供了启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.