小柯机器人

中国科学院生物物理研究所高璞等研究人员合作阐明人类SLC19A1对环状二核苷酸和叶酸的识别。这一研究成果于2022年10月20日在线发表在国际学术期刊《自然》上。

研究人员表示，环状二核苷酸（CDN）是所有生命领域中无处不在的信号分子。哺乳动物细胞在检测到细胞膜DNA信号时由环状GMP-AMP合成酶产生一种CDN，即2'3'-cGAMP。2'3'-cGAMP以及细菌和合成的CDN类似物可以作为第二信使激活干扰素基因的刺激物（STING）并引起广泛的下游反应。细胞外的CDN必须穿过细胞膜来激活STING，这一过程严重依赖溶质载体SLC19A1。此外，SLC19A1代表了叶酸营养物质和抗叶酸治疗剂的主要转运体，从而使SLC19A1成为多种生理和病理过程的关键因素。SLC19A1如何识别和转运CDN和叶酸/抗坏血酸尚不清楚。

研究人员报告了人SLC19A1（hSLC19A1）在无底物状态下以及与不同来源的多种CDN、一种主要的天然叶酸和一种新一代抗叶酸药物复合时的冷冻电镜结构。结构和诱变结果表明，hSLC19A1利用独特但不同的机制来识别CDN和叶酸类底物。两个CDN分子作为一个紧凑的双分子单元结合在hSLC19A1空腔内，而叶酸或抗叶酸则作为一个单体结合，占据空腔的一个独特口袋。此外，这些结构允许对hSLC19A1的活性丧失和疾病相关的突变进行准确的映射和潜在的机制解释。这项工作为理解SLC19家族转运体的机制提供了一个框架，并可作为开发潜在治疗药物的基础。

附：英文原文

Title: Recognition of cyclic dinucleotides and folates by human SLC19A1

Author: Zhang, Qixiang, Zhang, Xuyuan, Zhu, Yalan, Sun, Panpan, Zhang, Liwei, Ma, Junxiao, Zhang, Yong, Zeng, Lingan, Nie, Xiaohua, Gao, Yina, Li, Zhaolong, Liu, Songqing, Lou, Jizhong, Gao, Ang, Zhang, Liguo, Gao, Pu

Issue&Volume: 2022-10-20

Abstract: Cyclic dinucleotides (CDNs) are ubiquitous signaling molecules in all domains of life1,2. Mammalian cells produce one CDN, 2'3'-cGAMP, by cyclic GMP-AMP synthase upon detecting cytosolic DNA signals3-7. 2'3'-cGAMP, as well as bacterial and synthetic CDN analogs, can act as second messengers to activate stimulator of interferon genes (STING) and elicit broad downstream responses8-21. Extracellular CDNs must traverse the cell membrane to activate STING, a process that is critically dependent on the solute carrier SLC19A122,23. In addition, SLC19A1 represents the major transporter for folate nutrients and antifolate therapeutics24,25, thereby placing SLC19A1 as a key factor in multiple physiological and pathological processes. How SLC19A1 recognizes and transports CDNs and folate/antifolate is unknown. Here we report cryo-electron microscopy structures of human SLC19A1 (hSLC19A1) in a substrate-free state and in complexes with multiple CDNs from different sources, a predominant natural folate, and a new-generation antifolate drug. Structural and mutagenesis results demonstrate that hSLC19A1 utilizes unique yet divergent mechanisms to recognize CDN- and folate-type substrates. Two CDN molecules bind within the hSLC19A1 cavity as a compact dual-molecule unit, while folate or antifolate binds as a monomer and occupies a distinct pocket of the cavity. Moreover, the structures allow accurate mapping and potential mechanistic interpretation of loss-of-activity and disease-related mutations of hSLC19A1. Our work provides a framework for understanding the mechanism of SLC19 family transporters and serves as a foundation for the development of potential therapeutics.

DOI: 10.1038/s41586-022-05452-z

Source: https://www.nature.com/articles/s41586-022-05452-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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