SARS-CoV-2 spike protein mutations

From Proteopedia

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Revision as of 23:40, 27 January 2021

SARS-CoV-2 stands for Severe Acute Respiratory Syndrome - Corona Virus 2. The SARS-CoV-2 coronavirus causes COVID-19 (COrona VIrus Disease 2019). SARS-CoV-2 was numbered "2" because another coronavirus, SARS-CoV, caused an epidemic in 2002-2003. The genes of SARS-CoV-2 are in RNA. Viruses with RNA genomes tend to mutate faster than do viruses with DNA genomes^[1]^[2]. For example, a new influenza vaccine is needed every year due to mutations, and a single drug against HIV quickly becomes ineffective due to mutations. It is no surprise that SARS-CoV-2 is mutating.

1 Spike Protein
2 Mutant Lineages Emerging
3 Mutations Most Concerning
4 Vaccine Effectiveness Under Investigation
5 No Evidence for Increased Virulence
6 National Borders Temporarily Closed
7 Mutant Lineages Are Already Widely Disseminated

Spike Protein

plays a crucial role in attachment to host cells, by binding to the ACE-2 receptors on host cells. Spike protein is also the key player in fusion between the virus and host cell membranes, which delivers the virus genes into the cell, initiating infection.

Spike protein is a homotrimer assembled from 3 sequence-identical protein chains, here pink, green, and blue.
Mutations of concern in B.1.1.7 (black): see details below. (.)
Amino acids that bind ACE-2 (Details).
Furin cleavage site for priming (Details).

Rotate to view the animation from all sides (drag to rotate). Zoom the molecule with your mouse wheel, or Shift-Drag up/down. Click the green links to change the molecular scene: Scroll down in this frame.

Mutant Lineages Emerging

In December, 2020, scientists in the United Kingdom discovered that among thousands of mutations in SARS-CoV-2 detected in the UK and elsewhere, coronavirus with a particular set of mutations appeared to be rapidly becoming the predominant lineage^[3] for new infections in parts of England^[4]^[5]^[6]. This lineage is termed B.1.1.7 or VOC 202012/01^[7]^[6]. It is the first well charactized mutant lineage recognized late in the pandemic (see Note 1).

In late December, 2020, there was news from South Africa of another lineage becoming prevalent there, termed 501.V2^[8], 501Y.V2, or B.1.351^[9].

In December, 2020, many scientists believed that B.1.1.7 is more contagious^[7], but there remained some uncertainty, since the increase in B.1.1.7 could also be related to founder effects or variations in human behaviors in regions of England^[10]. However, by early January, 2021, it appeared very likely that B.1.1.7 and 501.V2 are more contagious^[11].

In January, 2021, a lineage with mutation L452R was reported to be expanding rapidly in Northern California, USA^[12]. From late 2020 into early 2021, this lineage expanded from 4% of samples to 25%^[13].

Also in January, 2021, the lineage P.1 was found to have increased rapidly in Manaus, Brazil^[14]^[15]. P.1 has 10 mutations in the spike protein, including 3 in common with the South African lineage 501.V2 (N501Y, K417N, and E484K)^[15]. P.1 was found in the USA in January, 2021^[14].

Mutations Most Concerning

B.1.1.7

Four mutations in the outer surface of the spike protein are of particular concern in B.1.1.7^[4]^[5]:

1. (See 3- and 1-letter amino acid abbreviations.) This mutation is in the receptor-binding domain of spike protein, and increases binding affinity for ACE-2, the receptor that SARS-CoV-2 uses to enter and infect cells^[16]^[17]^[18].

2 & 3: . These deletions are in a position likely to affect the ability of certain antibodies to block infection. However, since vaccination induces antibodies to many parts of the spike protein, these mutations alone are unlikely to reduce the effectiveness of the current vaccines (see below). These deletions have been useful in epidemiologic screening for B.1.1.7 without needing to sequence all samples^[19].

4. . This mutation is in the furin cleavage site that primes spike protein. The effects of this mutation are not yet known.

501.V2

The 501.V2 lineage (also called B.1.351) accounted for more than half of new cases in South Africa in late December, 2020^[8]. This lineage is also suspected to have a higher rate of transmission. Its mutations of greatest concern include one in common with B.1.1.7 (N501Y) plus two different mutations that are, like N501Y, in the receptor binding domain of the spike protein:

^[8].

These mutations also increase binding affinity for ACE2^[18]. Unlike B.1.1.7, 501.V2 retains His 69 and Val 70 (not deleted)^[9].

L452R

The lineage including spike protein mutation L452R increased from 4% to 25% of samples in Northern California, USA, by mid-January, 2021^[12]^[13]. L452R confers resistance to convalescent serum antibodies^[20], but its effect on T cell immunity is not known.

Vaccine Effectiveness Under Investigation

While the mutations in B.1.1.7 seem unlikely to make current anti-COVID-19 vaccines less effective, there is more concern regarding the additional mutations in 501.V2^[21], and investigations are beginning^[22]. Unfortunately, poor management of COVID-19 and inconsistent therapy maneuvers have favored development of mutations that may evade the initial wave of vaccines^[23]. Antibodies in the blood of half of people who have recovered from COVID-19 are unable to neutralize 501.V2^[24], but other forms of immunity, such as T-cells, may still be protective. Experts believe that present vaccines could be modified for greater effectiveness against these mutants, if necessary, withinin a few months^[21]^[22]. Moderna began development of a vaccine modified to combat 501.V2 in January, 2021^[25].

No Evidence for Increased Virulence

As of late December, 2020, there is no evidence that circulating mutations of SARS-CoV-2 cause more severe COVID-19, but this remains under investigation. B.1.1.7, in particular, does not increase hospitalization or death compared to the wild type SARS-CoV-2^[6].

National Borders Temporarily Closed

Being at the forefront of SARS-CoV-2 science may have caused unnecessary problems for the UK. Shortly after B.1.1.7 was reported, France closed its borders to the UK^[26]^[27]. This caused stranding of truck drivers who are citizens of EU countries shortly before Christmas, and concerns about food supplies.

Mutant Lineages Are Already Widely Disseminated

However, even in mid-December, 2020, it seemed likely that B.1.1.7 or similar lineages were already spreading in many countries around the world -- whether they were imported or arose semi-independently. Reuters reported "Cases of the new strain have also been detected in some other countries, including Denmark and Italy. Experts said the prevalence in Britain might be down to better detection."^[27] John Edmunds (Professor of Infectious Disease Disease Epidemiology, London School of Hygiene and Tropical Medicine) noted that the UK has "one of the most comprehensive and sensitive molecular surveillance systems in the world and that allowed us to pick up this strain relatively quickly."^[28] He refers to the UK's COVID-19 Genomics Consortium (COG-UK)^[29]^[30].

By the end of December, 2020, B.1.1.7 had been detected in at least 18 countries^[31], plus the United States^[32]. By January 18, 2021, B.1.1.7 infections were detected in 20 states of the United States^[33].

1 Movies for Slides
2 Acknowledgements
3 Update History
4 See Also
5 Notes
6 References

Movies for Slides

The movie at right (a multi-GIF, not interactive) can be dropped into a slide (Powerpoint, slides.google.com, libre office, etc.). It will animate when the slide is projected ("slide show" mode). This shows the priming conformational change, whereas the interactive scenes above show the static open conformation. The scenes above show all atoms, while the movie shows only alpha carbons. As above for lineage B.1.1.7: each chain of the homo-trimer is a different color; Four mutations (black); ACE2 binding site; furin cleavage site. To DOWNLOAD these files, right click, then save link as:

464 pixels, HIGH RESOLUTION, 6.9 MB (not shown).
300 pixels (low resolution, 3.1 MB) shown at right.

Please credit Proteopedia.Org in accord with our license, and Wrobel and coworkers^[34] for their cryo-EM structures.

Acknowledgements

Thanks to Shoshana Wodak, Iddo Friedberg, S. Krishnaswamy and Joel Sussman for suggestions that improved this article. Eric Martz wishes to thank Jaime Prilusky and Joel Sussman for their constant efforts over more than a decade that have made Proteopedia what it is today. Thanks also to the newer members of the Proteopedia:Team.

Update History

This article was initially posted December 22, 2020. Subsequent updates:

December 23, 2020: Full name of SARS corrected. Citation added^[17].
December 24, 2020: Added further evidence of the international pre-eminence of the UK coronavirus sequencing consortium^[28]^[29]. Added Acknowledgements.
December 25, 2020: Added two citations^[7]^[10] and added mention of the South African lineage without specific mutations.
December 27, 2020: Added this section Update History. Named and visualized the specific mutations of concern in the South African lineage 501.V2, with a new citation^[8].
December 29, 2020: Added two references documenting detection of B.1.1.7 in at least 19 countries^[31]^[32].
December 30, 2020: Added study showing no increased hospitalization or death for B.1.1.7 compared to wild type SARS-CoV-2^[6].
January 4, 2021: Added evidence that the mutant lineages are more contagious^[11].
January 5, 2021: Added a new subsection about concerns over vaccine effectiveness, with two new references^[21]^[22].
January 6, 2021: Cited analysis of events that have inadvertently favored mutations to evade vaccine effectiveness^[23].
January 7, 2021: Added a preprint showing that some of the mutations in B.1.1.7 and 501.V2 increase binding affinity between the spike protein and its receptor ACE2^[18].
January 9, 2021: Added alternate name B.1.351 for 501.V2^[9].
January 20, 2021: B.1.1.7 detected in 20 US states^[33]. Added L452R lineage^[12]^[13]^[20].
January 25, 2021: Convalescent plasma often ineffective against 501.V2^[24] and Moderna developing variant vaccine^[25].
January 27, 2021: Mentioned D614G that became prevalent during the onset of the pandemic. See Note 1. Cited definition of lineage^[3]. Mentioned epidemiological screening utility of deletions H67,V70^[19].

Notes

Note 1. The mutation D614G became predominant very early in the pandemic, before April, 2020^[35]. It is not discussed above, as the purpose of this article is to show mutations that occurred months into the worldwide pandemic, after vaccine development was well underway.

References

↑ Duffy S. Why are RNA virus mutation rates so damn high? PLoS Biol. 2018 Aug 13;16(8):e3000003. doi: 10.1371/journal.pbio.3000003., eCollection 2018 Aug. PMID:30102691 doi:http://dx.doi.org/10.1371/journal.pbio.3000003
↑ Borderia AV, Rozen-Gagnon K, Vignuzzi M. Fidelity Variants and RNA Quasispecies. Curr Top Microbiol Immunol. 2016;392:303-22. doi: 10.1007/82_2015_483. PMID:26499340 doi:http://dx.doi.org/10.1007/82_2015_483
↑ ^3.0 ^3.1 Rambaut A, Holmes EC, O'Toole A, Hill V, McCrone JT, Ruis C, du Plessis L, Pybus OG. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nat Microbiol. 2020 Nov;5(11):1403-1407. doi: 10.1038/s41564-020-0770-5. Epub, 2020 Jul 15. PMID:32669681 doi:http://dx.doi.org/10.1038/s41564-020-0770-5
↑ ^4.0 ^4.1 Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations, a report on behalf of the COVID-19 Genomics Consortium UK (CoG-UK).
↑ ^5.0 ^5.1 COG-UK update on SARS-CoV-2 Spike mutations of special interest. Report 1., December 20, 2020.
↑ ^6.0 ^6.1 ^6.2 ^6.3 Investigation of novel SARS-CoV-2 variant. Variant of Concern 202012/01. Technical briefing 2. published December 28, 2020 by Public Health England.
↑ ^7.0 ^7.1 ^7.2 NERVTAG/SPI-M Extraordinary meetingon SARS-CoV-2 variant of concern 202012/01 (variant B.1.1.7), December 21, 2020, from the UK Government New and Emerging Respiratory Virus Threats Advisory Group.
↑ ^8.0 ^8.1 ^8.2 ^8.3 Novel variant 501.V2 with triple spike receptor binding site substit[utions posted December 21, 2020 by the GSAID Influenza and Coronavirus sequences Initiative.
↑ ^9.0 ^9.1 ^9.2 Emerging SARS-CoV-2 Variants, CDC report, update of January 3, 2021.
↑ ^10.0 ^10.1 SARS-CoV-2 UK variant: Does it matter?, a 25 min video explanation recorded December 21, 2020, by Vincent Racaniello, Professor of virology at Columbia University, New York City.
↑ ^11.0 ^11.1 A simple chart shows why the new coronavirus variants are so worrisome, David Leonhardt, New York Times, January 4, 2021. A chart of new daily coronavirus cases shows Britain and South Africa surging, far exceeding rates in neighboring countries.
↑ ^12.0 ^12.1 ^12.2 COVID-19 Variant First Found in Other Countries and States Now Seen More Frequently in California, January 17, 2021, Santa Clara County Public Health, California, USA.
↑ ^13.0 ^13.1 ^13.2 Another New Covid-19 Variant Discovered In L.A. Might Be Vaccine Resistant, Researcher Says; Strain First Identified In Denmark by Tom Tapp in Deadline, January 18, 2021.
↑ ^14.0 ^14.1 A Guide to Emerging SARS-CoV-2 Variants by Katarina Zimmer, The Scientist, January 26, 2021.
↑ ^15.0 ^15.1 Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings, Nuno R. Faria et al. on behalf of the CADDE Genomic Networ,, January 12, 2021.
↑ Starr TN, Greaney AJ, Hilton SK, Ellis D, Crawford KHD, Dingens AS, Navarro MJ, Bowen JE, Tortorici MA, Walls AC, King NP, Veesler D, Bloom JD. Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding. Cell. 2020 Sep 3;182(5):1295-1310.e20. doi: 10.1016/j.cell.2020.08.012. Epub 2020, Aug 11. PMID:32841599 doi:http://dx.doi.org/10.1016/j.cell.2020.08.012
↑ ^17.0 ^17.1 Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants, preprint posted December 17, 2020 by Teruel, Maihot & Najmanovich. Computational work suggests that N501Y increases the occupancy of the open (primed) state of the spike protein.
↑ ^18.0 ^18.1 ^18.2 SARS-CoV-2 RBD in vitro evolution follows contagious mutation spread, yet generates an able infection inhibitor by Jiri Zahradnik et al., preprint posted January 6, 2020.
↑ ^19.0 ^19.1 The SARS-CoV-2 B.1.1.7 lineage: Summary of evidence from the U.K. by Moritz Gerstung of EMBL-EBI et al., January 20, 2021.
↑ ^20.0 ^20.1 Liu Z, VanBlargan LA, Rothlauf PW, Bloyet LM, Chen RE, Stumpf S, Zhao H, Errico JM, Theel ES, Ellebedy AH, Fremont DH, Diamond MS, Whelan SPJ. Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization. bioRxiv. 2020 Nov 8. doi: 10.1101/2020.11.06.372037. PMID:33442690 doi:http://dx.doi.org/10.1101/2020.11.06.372037
↑ ^21.0 ^21.1 ^21.2 Expert reaction to the South African variant, Science Media Centre of the UK, January 4, 2021.
↑ ^22.0 ^22.1 ^22.2 South African SARS-CoV-2 Variant Alarms Scientists, Max Kozlov, The Scientist, January 5, 2021.
↑ ^23.0 ^23.1 Musings of an anonymous, pissed off virologist by Paul Bieniasz, Professor at Rockefeller University, January 5, 2021.
↑ ^24.0 ^24.1 SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma, preprint posted January 19, 2021.
↑ ^25.0 ^25.1 Moderna is designing a new version of its COVID-19 shot to fight the variant first found in South Africa by Andrew Dunn and Allison DeAngelis, Business Insider, January 25, 2021.
↑ A new coronavirus strain surging to dominance in the UK appears to spread faster despite lockdowns, prompting panic and a wave of border closures, Business Insider, December 21, 2020.
↑ ^27.0 ^27.1 France to reopen border with England for COVID-clear travellers, Reuters, December 22, 2020.
↑ ^28.0 ^28.1 We need even tougher curbs to fight this new coronavirus strain by John Edmunds, The Guardian, December 20, 2020.
↑ ^29.0 ^29.1 COVID-19 Genomics UK (COG-UK) Consortium, Wellcome Sanger Institute, UK.
↑ COVID-19 Genomics Consortium UK (CoG-UK).
↑ ^31.0 ^31.1 These are all countries that have already reported cases of the new, possibly more infectious coronavirus variant from the UK, Business Insider, December 29, 2020.
↑ ^32.0 ^32.1 New COVID-19 Variant From U.K. Confirmed In U.S. For First Time, Huffington Post, December 29, 2020.
↑ ^33.0 ^33.1 US COVID-19 Cases Caused by Variants, update of January 18, 2021. Centers for Disease Control and Prevention, USA.
↑ Wrobel AG, Benton DJ, Xu P, Roustan C, Martin SR, Rosenthal PB, Skehel JJ, Gamblin SJ. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat Struct Mol Biol. 2020 Jul 9. pii: 10.1038/s41594-020-0468-7. doi:, 10.1038/s41594-020-0468-7. PMID:32647346 doi:http://dx.doi.org/10.1038/s41594-020-0468-7
↑ Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, Hengartner N, Giorgi EE, Bhattacharya T, Foley B, Hastie KM, Parker MD, Partridge DG, Evans CM, Freeman TM, de Silva TI, McDanal C, Perez LG, Tang H, Moon-Walker A, Whelan SP, LaBranche CC, Saphire EO, Montefiori DC. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell. 2020 Aug 20;182(4):812-827.e19. doi: 10.1016/j.cell.2020.06.043. Epub 2020 , Jul 3. PMID:32697968 doi:http://dx.doi.org/10.1016/j.cell.2020.06.043

Proteopedia Page Contributors and Editors (what is this?)

Eric Martz

Retrieved from "http://52.214.119.220/wiki/index.php/SARS-CoV-2_spike_protein_mutations"

@@ Line 25: / Line 25: @@
 In January, 2021, a lineage with mutation '''L452R''' was reported to be expanding rapidly in Northern California, USA<ref name="santaclara">[https://www.sccgov.org/sites/covid19/Pages/press-release-01-17-2021-COVID-19-variant-more-frequent-in-CA.aspx COVID-19 Variant First Found in Other Countries and States Now Seen More Frequently in California], January 17, 2021, Santa Clara County Public Health, California, USA.</ref>. From late 2020 into early 2021, this lineage expanded from 4% of samples to 25%<ref name="deadline">[https://deadline.com/2021/01/another-new-covid-19-variant-in-l-a-vaccine-resistant-denmark-1234675834/ Another New Covid-19 Variant Discovered In L.A. Might Be Vaccine Resistant, Researcher Says; Strain First Identified In Denmark] by Tom Tapp in ''Deadline'', January 18, 2021.</ref>.
-Also in January, 2021, the lineage '''P.1''' was found to have increased rapidly in Manaus, Brazil<ref name="P1.1">[https://www.the-scientist.com/news-opinion/a-guide-to-emerging-sars-cov-2-variants-68387 A Guide to Emerging SARS-CoV-2 Variants] by Katarina Zimmer, ''The Scientist'', January 26, 2021.</ref>. P.1 has 10 mutations in the spike protein, including 3 in common with the South African lineage 501.V2 (N501Y, K417N, and E484K)<ref name="P1.1" />.
+Also in January, 2021, the lineage '''P.1''' was found to have increased rapidly in Manaus, Brazil<ref name="P1.1">[https://www.the-scientist.com/news-opinion/a-guide-to-emerging-sars-cov-2-variants-68387 A Guide to Emerging SARS-CoV-2 Variants] by Katarina Zimmer, ''The Scientist'', January 26, 2021.</ref><ref name="manaus1" />. P.1 has 10 mutations in the spike protein, including 3 in common with the South African lineage 501.V2 (N501Y, K417N, and E484K)<ref name="manaus1">[https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings], Nuno R. Faria ''et al.'' on behalf of the CADDE Genomic Networ,, January 12, 2021.</ref>. P.1 was found in the USA in January, 2021<ref name="P1.1" />.
 ===Mutations Most Concerning===