Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1

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ABSTRACT

Nonstructural protein 1 (Nsp1) of severe acute respiratory syndrome coronaviruses (SARS-CoVs) is an important pathogenic factor that inhibits host protein translation by means of its C terminus. However, its N-terminal function remains elusive. Here, we determined the crystal structure of the N terminus (amino acids [aa] 11 to 125) of SARS-CoV-2 Nsp1 at a 1.25-Å resolution. Further functional assays showed that the N terminus of SARS-CoVs Nsp1 alone loses the ability to colocalize with ribosomes and inhibit protein translation. The C terminus of Nsp1 can colocalize with ribosomes, but its protein translation inhibition ability is significantly weakened. Interestingly, fusing the C terminus of Nsp1 with enhanced green fluorescent protein (EGFP) or other proteins in place of its N terminus restored the protein translation inhibitory ability to a level equivalent to that of full-length Nsp1. Thus, our results suggest that the N terminus of Nsp1 is able to stabilize the binding of the Nsp1 C terminus to ribosomes and act as a nonspecific barrier to block the mRNA channel, thus abrogating host mRNA translation.

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

Theo M. Bestebroer, Albert Osterhaus, Sander van Boheemen … (2012)

A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.

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Author and article information

Contributors

Yuchen Xia:

ORCID: https://orcid.org/0000-0001-8460-3893

Yan Li

Miguel Angel Martinez: Role: Editor

Journal

Journal ID (nlm-ta): Microbiol Spectr

Journal ID (iso-abbrev): Microbiol Spectr

Journal ID (publisher-id): spectrum

Title: Microbiology Spectrum

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2165-0497

Publication date (Electronic, pub): 16 June 2021

Publication date (Electronic, collection): Jul-Aug 2021

Volume: 9

Issue: 1

Electronic Location Identifier: e00169-21

Affiliations

[a ] State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, School of Basic Medical Sciences, Wuhan University, Wuhan, China

[b ] Department of Blood Transfusion, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China

[c ] Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

[d ] Faculty of Science (Medical Science), The University of Sydney, Sydney, New South Wales, Australia

[e ] School of Biological Sciences, Nanyang Technological University, Singapore

[f ] BioBank, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

[g ] MRC Centre for Molecular Bacteriology and Infection, Imperial College London, United Kingdom

[h ] Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology, Wuhan, China

Fundacio irsiCaixa

Author notes

Kaitao Zhao, Zunhui Ke, and Hongbing Hu contributed equally to this work. Author order was determined both alphabetically and in order of increasing seniority.

Citation Zhao K, Ke Z, Hu H, Liu Y, Li A, Hua R, Guo F, Xiao J, Zhang Y, Duan L, Yan X-F, Gao Y-G, Liu B, Xia Y, Li Y. 2021. Structural basis and function of the N terminus of SARS-CoV-2 nonstructural protein 1. Microbiol Spectr 9:e00169-21. https://doi.org/10.1128/Spectrum.00169-21.

Author information

Kaitao Zhao https://orcid.org/0000-0002-0261-1599

Yuchen Xia https://orcid.org/0000-0001-8460-3893

Article

Publisher ID: 00169-21

DOI: 10.1128/Spectrum.00169-21

PMC ID: 8552758

PubMed ID: 34132580

SO-VID: 21c4621f-a110-4638-bec6-10944321b55d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 4 May 2021

Date accepted : 12 May 2021

Page count

supplementary-material: 0, Figures: 5, Tables: 0, Equations: 0, References: 38, Pages: 11, Words: 6823

Funding

Funded by: National Natural Science Foundation of China (NSFC), FundRef https://doi.org/10.13039/501100001809;

Award ID: 81971936

Award Recipient : Yuchen Xia

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cover-date July/August 2021

Keywords: n terminus,nsp1,sars-cov-2,crystal structure,protein translation,ribosome

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Keywords: n terminus, nsp1, sars-cov-2, crystal structure, protein translation, ribosome

Structural Basis and Function of the N Terminus of SARS-CoV-2 Nonstructural Protein 1

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Novel Coronavirus Disease COVID-19

Most cited references 38

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.

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