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人IPS-1/MAVS/VISA/Cardif半胱天冬酶激活募集结构域的晶体结构

Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain.

作者信息

Potter Jane A, Randall Richard E, Taylor Garry L

机构信息

Centre for Biomolecular Sciences, University of St Andrews, St Andrews, Fife, KY16 9ST, UK.

出版信息

BMC Struct Biol. 2008 Feb 28;8:11. doi: 10.1186/1472-6807-8-11.

DOI:10.1186/1472-6807-8-11
PMID:18307765
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2291057/
Abstract

BACKGROUND

IPS-1/MAVS/VISA/Cardif is an adaptor protein that plays a crucial role in the induction of interferons in response to viral infection. In the initial stage of the intracellular antiviral response two RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-association gene 5 (MDA5), are independently able to bind viral RNA in the cytoplasm. The 62 kDa protein IPS-1/MAVS/VISA/Cardif contains an N-terminal caspase activation and recruitment (CARD) domain that associates with the CARD regions of RIG-I and MDA5, ultimately leading to the induction of type I interferons. As a first step towards understanding the molecular basis of this important adaptor protein we have undertaken structural studies of the IPS-1 MAVS/VISA/Cardif CARD region.

RESULTS

The crystal structure of human IPS-1/MAVS/VISA/Cardif CARD has been determined to 2.1A resolution. The protein was expressed and crystallized as a maltose-binding protein (MBP) fusion protein. The MBP and IPS-1 components each form a distinct domain within the structure. IPS-1/MAVS/VISA/Cardif CARD adopts a characteristic six-helix bundle with a Greek-key topology and, in common with a number of other known CARD structures, contains two major polar surfaces on opposite sides of the molecule. One face has a surface-exposed, disordered tryptophan residue that may explain the poor solubility of untagged expression constructs.

CONCLUSION

The IPS-1/MAVS/VISA/Cardif CARD domain adopts the classic CARD fold with an asymmetric surface charge distribution that is typical of CARD domains involved in homotypic protein-protein interactions. The location of the two polar areas on IPS-1/MAVS/VISA/Cardif CARD suggest possible types of associations that this domain makes with the two CARD domains of MDA5 or RIG-I. The N-terminal CARD domains of RIG-I and MDA5 share greatest sequence similarity with IPS-1/MAVS/VISA/Cardif CARD and this has allowed modelling of their structures. These models show a very different charge profile for the equivalent surfaces compared to IPS-1/MAVS/VISA/Cardif CARD.

摘要

背景

IPS-1/MAVS/VISA/Cardif是一种衔接蛋白，在病毒感染诱导干扰素产生过程中起关键作用。在细胞内抗病毒反应的初始阶段，两种RNA解旋酶，即视黄酸诱导基因I（RIG-I）和黑色素瘤分化相关基因5（MDA5），能够在细胞质中独立结合病毒RNA。62 kDa的蛋白质IPS-1/MAVS/VISA/Cardif含有一个N端半胱天冬酶激活和募集（CARD）结构域，该结构域与RIG-I和MDA5的CARD区域结合，最终导致I型干扰素的诱导。作为理解这一重要衔接蛋白分子基础的第一步，我们对IPS-1 MAVS/VISA/Cardif CARD区域进行了结构研究。

结果

人IPS-1/MAVS/VISA/Cardif CARD的晶体结构已确定至2.1埃分辨率。该蛋白作为麦芽糖结合蛋白（MBP）融合蛋白表达并结晶。MBP和IPS-1组分在结构中各自形成一个独特的结构域。IPS-1/MAVS/VISA/Cardif CARD采用具有希腊钥匙拓扑结构的特征性六螺旋束，并且与许多其他已知的CARD结构一样，在分子相对的两侧包含两个主要的极性表面。其中一个表面有一个暴露于表面的无序色氨酸残基，这可能解释了未标记表达构建体溶解性差的原因。

结论

IPS-1/MAVS/VISA/Cardif CARD结构域采用经典的CARD折叠，表面电荷分布不对称，这是参与同型蛋白质-蛋白质相互作用的CARD结构域的典型特征。IPS-1/MAVS/VISA/Cardif CARD上两个极性区域的位置表明该结构域与MDA5或RIG-I的两个CARD结构域可能的结合类型。RIG-I和MDA5的N端CARD结构域与IPS-1/MAVS/VISA/Cardif CARD具有最大的序列相似性，这使得能够对它们的结构进行建模。这些模型显示，与IPS-1/MAVS/VISA/Cardif CARD相比，等效表面的电荷分布非常不同。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/df2747ccb975/1472-6807-8-11-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/f88711923218/1472-6807-8-11-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/a3955a65e021/1472-6807-8-11-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/24308f7efd5e/1472-6807-8-11-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/df2747ccb975/1472-6807-8-11-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/f88711923218/1472-6807-8-11-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/a3955a65e021/1472-6807-8-11-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/24308f7efd5e/1472-6807-8-11-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f61/2291057/df2747ccb975/1472-6807-8-11-4.jpg

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