硅学证据表明,在 TMPRSS2 同工酶 1 的一个常见变体中用甘氨酸取代缬氨酸(p.G8V)增加了内细胞信号的可及性:这与 SARS-CoV-2 进入宿主细胞和对 COVID-19 的易感性有关。

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Matteo Calcagnile , Fabrizio Damiano , Giambattista Lobreglio , Luisa Siculella , Maria Pia Bozzetti , Patricia Forgez , Alexandra Malgoyre , Nicolas Libert , Cecilia Bucci , Marco Alifano , Pietro Alifano
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引用次数: 0

摘要

TMPRSS2 蛋白酶在 SARS-CoV-2 进入细胞中起着关键作用。rs75603675 (c.23G>T)是一个错义变异,会导致 TMPRSS2 同工酶 1 第 8 位的甘氨酸被缬氨酸取代(p.G8V)。根据 GnomAD v4.0.0 数据库,rs75603675 的等位基因频率在全球范围内为 38.10%,在东亚人群中为 0.92%,在非芬兰裔欧洲人(NFE)人群中为 40.77%。我们在两组患者中分析了 rs75603675 的发生率,第一组是法国一家医院收治的重度/危重 COVID-19 患者(42 人),第二组是意大利一家医院收治的主要无症状/无症状/轻度 COVID-19 患者(69 人)。我们发现,两组患者的 TMPRSS2-c.23T 小等位基因频率相似,分别为 46.43% 和 46.38%,高于 NFE 群体的频率(40.77%)。当将两组患者的基因型数据(TMPRSS2-c.23T/c.23T 同型杂合子 + TMPRSS2-c.23G/c.23T 杂合子 vs. TMPRSS2-c.23G/c.23G 同型杂合子)汇总并与 NFE 群体的预期数据进行比较时,Chi-square 检验得出了显著的结果(p < 0.05),这表明 p.G8V 取代可能存在致病机制。我们探讨了 p.G8V 取代的可能影响,发现 TMPRSS2 异构体 1 的 N 端区域包含一个凝集素/AP-2 依赖性内吞的信号。硅学分析预测,p.G8V置换可能会增加内吞信号的可及性,从而有助于SARS-CoV-2进入细胞。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In silico evidence that substitution of glycine for valine (p.G8V) in a common variant of TMPRSS2 isoform 1 increases accessibility to an endocytic signal: Implication for SARS-cov-2 entry into host cells and susceptibility to COVID-19

The TMPRSS2 protease plays a key role in the entry of the SARS-CoV-2 into cells. The TMPRSS2 gene is highly polymorphic in humans, and some polymorphisms may affect the susceptibility to COVID-19 or disease severity. rs75603675 (c.23G > T) is a missense variant that causes the replacement of glycine with valine at position 8 (p.G8V) in the TMPRSS2 isoform 1. According to GnomAD v4.0.0 database, the allele frequency of the rs75603675 on a global scale is 38.10 %, and range from 0.92 % in East Asian to 40.77 % in non-Finnish European (NFE) population. We analyzed the occurrence of the rs75603675 in two cohorts of patients, the first with severe/critical COVID-19 enrolled in a French hospital (42 patients), and the second with predominantly asymptomatic/pauci-symptomatic/mild COVID-19 enrolled in an Italian hospital (69 patients). We found that the TMPRSS2-c.23T minor allele frequency was similar in the two cohorts, 46.43 % and 46.38 %, respectively, and higher than the frequency in the NFE population (40.77 %). Chi-square test provided significant results (p < 0.05) when the genotype data (TMPRSS2-c.23T/c.23T homozygotes + TMPRSS2-c.23G/c.23T heterozygotes vs. TMPRSS2-c.23G/c.23G homozygotes) of the two patient groups were pooled and compared to the expected data for the NFE population, suggesting a possible pathogenetic mechanism of the p.G8V substitution. We explored the possible effects of the p.G8V substitution and found that the N-terminal region of the TMPRSS2 isoform 1 contains a signal for clathrin/AP-2-dependent endocytosis. In silico analysis predicted that the p.G8V substitution may increase the accessibility to the endocytic signal, which could help SARS-CoV-2 enter cells.

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来源期刊
Biochimie
Biochimie 生物-生化与分子生物学
CiteScore
7.20
自引率
2.60%
发文量
219
审稿时长
40 days
期刊介绍: Biochimie publishes original research articles, short communications, review articles, graphical reviews, mini-reviews, and hypotheses in the broad areas of biology, including biochemistry, enzymology, molecular and cell biology, metabolic regulation, genetics, immunology, microbiology, structural biology, genomics, proteomics, and molecular mechanisms of disease. Biochimie publishes exclusively in English. Articles are subject to peer review, and must satisfy the requirements of originality, high scientific integrity and general interest to a broad range of readers. Submissions that are judged to be of sound scientific and technical quality but do not fully satisfy the requirements for publication in Biochimie may benefit from a transfer service to a more suitable journal within the same subject area.
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