Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses
Coronavirus genomes sequester their start codons within stem-loop 5 (SL5), a structured, 5' genomic RNA element. In most alpha- and betacoronaviruses, the secondary structure of SL5 is predicted to contain a four-way junction of helical stems, some of which are capped with UUYYGU hexaloops. Here, using cryogenic electron microscopy (cryo-EM) and computational modeling with biochemically-determined secondary structures, we present three-dimensional structures of SL5 from six coronaviruses. The SL5 domain of betacoronavirus SARS-CoV-2, resolved at 4.7 Å resolution, exhibits a T-shaped structure, with its UUYYGU hexaloops at opposing ends of a coaxial stack, the T's "arms." Further analysis of SL5 domains from SARS-CoV-1 and MERS (7.1 and 6.4-6.9 Å resolution, respectively) indicate that the junction geometry and inter-hexaloop distances are conserved features across the studied human-infecting betacoronaviruses. The MERS SL5 domain displays an additional tertiary interaction, which is also observed in the non-human-infecting betacoronavirus BtCoV-HKU5 (5.9-8.0 Å resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6.5 and 8.4-9.0 Å resolution, respectively), exhibit the same coaxial stacks, including the UUYYGU-capped arms, but with a phylogenetically distinct crossing angle, an X-shape. As such, all SL5 domains studied herein fold into stable tertiary structures with cross-genus similarities, with implications for potential protein-binding modes and therapeutic targets.
| Errataetall: |
UpdateIn: Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2320493121. - PMID 38427602 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 27. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kretsch, Rachael C [VerfasserIn] |
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| Links: |
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| Themen: |
Biological Sciences |
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| Anmerkungen: |
Date Revised 11.03.2024 published: Electronic UpdateIn: Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2320493121. - PMID 38427602 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.11.22.567964 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Tertiary folds of the SL5 RNA from the 5' proximal region of SARS-CoV-2 and related coronaviruses |
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| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Coronavirus genomes sequester their start codons within stem-loop 5 (SL5), a structured, 5' genomic RNA element. In most alpha- and betacoronaviruses, the secondary structure of SL5 is predicted to contain a four-way junction of helical stems, some of which are capped with UUYYGU hexaloops. Here, using cryogenic electron microscopy (cryo-EM) and computational modeling with biochemically-determined secondary structures, we present three-dimensional structures of SL5 from six coronaviruses. The SL5 domain of betacoronavirus SARS-CoV-2, resolved at 4.7 Å resolution, exhibits a T-shaped structure, with its UUYYGU hexaloops at opposing ends of a coaxial stack, the T's "arms." Further analysis of SL5 domains from SARS-CoV-1 and MERS (7.1 and 6.4-6.9 Å resolution, respectively) indicate that the junction geometry and inter-hexaloop distances are conserved features across the studied human-infecting betacoronaviruses. The MERS SL5 domain displays an additional tertiary interaction, which is also observed in the non-human-infecting betacoronavirus BtCoV-HKU5 (5.9-8.0 Å resolution). SL5s from human-infecting alphacoronaviruses, HCoV-229E and HCoV-NL63 (6.5 and 8.4-9.0 Å resolution, respectively), exhibit the same coaxial stacks, including the UUYYGU-capped arms, but with a phylogenetically distinct crossing angle, an X-shape. As such, all SL5 domains studied herein fold into stable tertiary structures with cross-genus similarities, with implications for potential protein-binding modes and therapeutic targets | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a Biological Sciences | |
| 650 | 4 | |a Biophysics and Computational Biology | |
| 650 | 4 | |a Comparative structural biology | |
| 650 | 4 | |a Coronaviruses | |
| 650 | 4 | |a Cryo-EM | |
| 650 | 4 | |a Viral RNA structure | |
| 700 | 1 | |a Xu, Lily |e verfasserin |4 aut | |
| 700 | 1 | |a Zheludev, Ivan N |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xueting |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Nye, Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Kaiming |e verfasserin |4 aut | |
| 700 | 1 | |a Chiu, Wah |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Rhiju |e verfasserin |4 aut | |
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