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使用由蛋白质工程启用的冷EM使用IFNλ4受体复合物的结构研究

William S Grubbe¹, Bixia Zhang², Aileen Kauffman¹

¹Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.

Nature communications

|January 18, 2025

概括

研究人员开发了一种方法来产生和结构性分析INTERFERON lambda 4 (IFNλ4),揭示其受体相互作用. 这一突破解释了IFNλ4对病毒清除的矛盾影响,并使未来的治疗策略成为可能.

科学领域:

免疫学免疫学免疫学
结构生物学结构生物学
病毒学病毒学

背景情况:

2013年发现的干扰素兰巴达4 (IFNλ4) 与病毒清除问题有关.
以前的结构和功能研究受限于蛋白质生产中的困难.
了解IFNλ4的矛盾行为需要详细的结构和功能特征.

研究的目的:

开发一种强大的IFNλ4.4生产方法.
确定IFNλ4和IFNλ3与它们的受体复合的高分辨率结构.
阐明受体参与和信号的差异的结构基础.

主要方法:

强大的IFNλ4蛋白的生产.
酵母表面显示IL10Rβ的亲和力成熟.
低温电子显微镜 (cryo-EM) 用于解决IFNλ4/IFNλR1/IL10Rβ和IFNλ3/IFNλR1/IL10Rβ复合物的结构.
用于结构分析的分子建模和模拟.

主要成果:

成功生产和净化IFNλ4蛋白质.
确定了IFNλ4和IFNλ3与它们的受体 (IFNλR1和IL10Rβ) 结合的72kDa结构,分别分辨率为3.26 Å和3.00 Å.
在IFNλ4和IFNλ3复合体之间确定了明显的受体参与和受体几何中的12度旋转.
在IFNλ4中发现了一个独特的区域,在修改后,可以使蛋白质分泌.

结论:

该研究为IFNλ4.4提供了第一个结构和功能洞察力.
结构差异解释了细胞信号传递,基因诱导和抗病毒活动的变化.
这些发现为了解和潜在地纠正IFNλ4功能障碍铺平了道路.

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