SARS-CoV-2 spike protein fusion transformation
From Proteopedia
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<StructureSection load='' size='[300,400]' side='right' caption='' scene='85/857791/Morf_6xr8_6xra_theis_lin_cao/4'> | <StructureSection load='' size='[300,400]' side='right' caption='' scene='85/857791/Morf_6xr8_6xra_theis_lin_cao/4'> | ||
| + | ==Introduction== | ||
SARS-CoV-2 spike protein undergoes a dramatic conformational rearrangement (<scene name='85/857791/Morf_6xr8_6xra_theis_lin_cao/4'>restore initial scene</scene>) that plays a central role in fusing the coronavirus membrane with the host cell membrane<ref name="cai-zhang">PMID: 32694201</ref>. Similar conformational transformations have been observed for the spike protein of SARS-CoV<ref name="fan">PMID: 32681106</ref> and mouse hepatitis virus<ref name="walls">PMID: 29073020</ref>, among others. These rearrangements also have much in common with the membrane fusion mechansism of influenza hemagglutinin<ref name="pabis">PMID: 32188780</ref>. The molecular scenes in this article are based on the [[cryo-EM]] pre- and post-fusion structures of SARS-CoV-2 spike protein reported July, 2020, by Cai, Zhang and coworkers with the group of Bing Chen<ref name="cai-zhang" />. | SARS-CoV-2 spike protein undergoes a dramatic conformational rearrangement (<scene name='85/857791/Morf_6xr8_6xra_theis_lin_cao/4'>restore initial scene</scene>) that plays a central role in fusing the coronavirus membrane with the host cell membrane<ref name="cai-zhang">PMID: 32694201</ref>. Similar conformational transformations have been observed for the spike protein of SARS-CoV<ref name="fan">PMID: 32681106</ref> and mouse hepatitis virus<ref name="walls">PMID: 29073020</ref>, among others. These rearrangements also have much in common with the membrane fusion mechansism of influenza hemagglutinin<ref name="pabis">PMID: 32188780</ref>. The molecular scenes in this article are based on the [[cryo-EM]] pre- and post-fusion structures of SARS-CoV-2 spike protein reported July, 2020, by Cai, Zhang and coworkers with the group of Bing Chen<ref name="cai-zhang" />. | ||
| + | ==Pre-Fusion Structure== | ||
<center>{{Template:Green_links_zoom}}</center> | <center>{{Template:Green_links_zoom}}</center> | ||
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The <scene name='85/857791/Pre-fusion_6xr8/1'>SARS-CoV-2 spike protein pre-fusion conformation</scene> is a homo-trimer, each chain having a mature length of 1,261 amino acids. This pre-fusion cryo-EM structure [[6xr8]] is complete except for 110 residues of the C-terminus (narrow end), comprising 48 residues of the stem (heptad repeat 2 domain), a 23-residue trans-membrane domain, and a 39 residue cytoplasmic domain. | The <scene name='85/857791/Pre-fusion_6xr8/1'>SARS-CoV-2 spike protein pre-fusion conformation</scene> is a homo-trimer, each chain having a mature length of 1,261 amino acids. This pre-fusion cryo-EM structure [[6xr8]] is complete except for 110 residues of the C-terminus (narrow end), comprising 48 residues of the stem (heptad repeat 2 domain), a 23-residue trans-membrane domain, and a 39 residue cytoplasmic domain. | ||
| + | ===Domains=== | ||
<scene name='85/857791/Pre-fusion_6xr8/4'>Domains are colored</scene> as in Cai, Zhang ''et al''. <ref name="cai-zhang" /> ('''lengths'''): | <scene name='85/857791/Pre-fusion_6xr8/4'>Domains are colored</scene> as in Cai, Zhang ''et al''. <ref name="cai-zhang" /> ('''lengths'''): | ||
* S1 receptor binding region: | * S1 receptor binding region: | ||
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</center></td></tr></table> | </center></td></tr></table> | ||
</center> | </center> | ||
| - | + | ==Activation== | |
| - | A protease, typically [[furin]], cuts the chains at the position marked with <b><font color="#ff8080">Pink balls</font></b><ref name="cut1" />, but the assembly, now six chains, remains intact. The cut may facilitate [[SARS-CoV-2 spike protein priming by furin|extending one receptor binding domain]] to engage the ACE2 receptor. | + | A protease, typically [[furin]], cuts the chains at the position marked with <b><font color="#ff8080">Pink balls</font></b><ref name="cut1" />, but the assembly, now six chains, remains intact. The cut may facilitate [[SARS-CoV-2 spike protein priming by furin|extending one receptor binding domain]] to engage the ACE2 receptor. This "priming" cut divides each chain of protein S into an N-terminal '''S1''' receptor-binding fragment, and a C-terminal '''S2''' fusion fragment<ref name="cai-zhang" />. <scene name='85/857791/Pre-fusion_6xr8/5'>S1, here shown translucent</scene>, will later separate. |
Binding to ACE2 and a second proteolytic cut are believed to trigger release of S1<ref name="cai-zhang" />, after which <scene name='85/857791/Pre-fusion_6xr8/7'>only S2 remains attached to the virus membrane</scene> through the stem and transmembrane domains (absent in this model) that extend from the <font color="red">'''red balls'''</font>. | Binding to ACE2 and a second proteolytic cut are believed to trigger release of S1<ref name="cai-zhang" />, after which <scene name='85/857791/Pre-fusion_6xr8/7'>only S2 remains attached to the virus membrane</scene> through the stem and transmembrane domains (absent in this model) that extend from the <font color="red">'''red balls'''</font>. | ||
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| + | ==Limitations of Models== | ||
Next, a dramatic conformational transformation occurs that triggers membrane fusion. We will compare the pre-fusion cryo-EM model ([[6xr8]]) with the post-fusion model ([[6xra]]). However, these two models have only two protein segments in common, sequence ranges 703-770 and 912-1162. The parts of the pre-fusion model <scene name='85/857791/Pre-fusion_6xr8/8'>absent in the post-fusion model are here opaque (common parts translucent)</scene>. Thus, the pre- to post-fusion comparison will involve <scene name='85/857791/Pre-fusion_6xr8/9'>only the common portions</scene>. | Next, a dramatic conformational transformation occurs that triggers membrane fusion. We will compare the pre-fusion cryo-EM model ([[6xr8]]) with the post-fusion model ([[6xra]]). However, these two models have only two protein segments in common, sequence ranges 703-770 and 912-1162. The parts of the pre-fusion model <scene name='85/857791/Pre-fusion_6xr8/8'>absent in the post-fusion model are here opaque (common parts translucent)</scene>. Thus, the pre- to post-fusion comparison will involve <scene name='85/857791/Pre-fusion_6xr8/9'>only the common portions</scene>. | ||
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| + | ==Fusion== | ||
<b>Fusion of the virus and host cell membranes</b> seems to happen when the spike protein brings the virus membrane (near the <font color="red">'''red balls'''</font>) very close to the host membrane, after the host membrane is attached to the fusion peptide (near the <font color="#0060ff">'''blue balls'''</font>). | <b>Fusion of the virus and host cell membranes</b> seems to happen when the spike protein brings the virus membrane (near the <font color="red">'''red balls'''</font>) very close to the host membrane, after the host membrane is attached to the fusion peptide (near the <font color="#0060ff">'''blue balls'''</font>). | ||
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:(1) Aquisition of the host membrane appears to happen when <scene name='85/857791/Morf_6xr8_6xra_theis_lin_cao/5'>several pre-fusion helices combine to "spear" the host membrane</scene> with one long helix, having the fusion peptide at its end (near the <font color="#0060ff">'''blue balls'''</font>). (The fusion peptide is absent in this model.) | :(1) Aquisition of the host membrane appears to happen when <scene name='85/857791/Morf_6xr8_6xra_theis_lin_cao/5'>several pre-fusion helices combine to "spear" the host membrane</scene> with one long helix, having the fusion peptide at its end (near the <font color="#0060ff">'''blue balls'''</font>). (The fusion peptide is absent in this model.) | ||
<center> | <center> | ||
Revision as of 20:47, 5 August 2020
This page is under construction starting August 3, 2020. This red text will be removed when the page is completed.
The spike protein of SARS-CoV-2 plays a central role in coronavirus attachment to the ACE2 receptor on host cells, and in getting the RNA genome of the virus into the host cell via fusion of the virus and host cell membranes, initiating infection.
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See Also
Methods
The pre-fusion structure 6xr8 was morphed to the post-fusion structure 6xra by linear interpolation, requesting 14 intermediate frames (16 total), using the server provided by Karsten Theis after another method[6] gave unsatisfactory results. This produced an 11 MB file, which took 25 sec to load into JSmol. Each script took a minimum of 8 sec to complete. To reduce both the bulk of this file and the processing times for JSmol, the alpha carbons were extracted (along with the MODEL and ENDMDL records) by deleting all other lines in the PDB file[7]. The resulting 16 model morph PDB file is Image:Morf-6xr8-6xra-theis-cao.pdb.
References and Notes
- ↑ 1.0 1.1 1.2 1.3 1.4 Cai Y, Zhang J, Xiao T, Peng H, Sterling SM, Walsh RM Jr, Rawson S, Rits-Volloch S, Chen B. Distinct conformational states of SARS-CoV-2 spike protein. Science. 2020 Jul 21. pii: science.abd4251. doi: 10.1126/science.abd4251. PMID:32694201 doi:http://dx.doi.org/10.1126/science.abd4251
- ↑ Fan X, Cao D, Kong L, Zhang X. Cryo-EM analysis of the post-fusion structure of the SARS-CoV spike glycoprotein. Nat Commun. 2020 Jul 17;11(1):3618. doi: 10.1038/s41467-020-17371-6. PMID:32681106 doi:http://dx.doi.org/10.1038/s41467-020-17371-6
- ↑ Walls AC, Tortorici MA, Snijder J, Xiong X, Bosch BJ, Rey FA, Veesler D. Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11157-11162. doi:, 10.1073/pnas.1708727114. Epub 2017 Oct 3. PMID:29073020 doi:http://dx.doi.org/10.1073/pnas.1708727114
- ↑ Pabis A, Rawle RJ, Kasson PM. Influenza hemagglutinin drives viral entry via two sequential intramembrane mechanisms. Proc Natl Acad Sci U S A. 2020 Mar 31;117(13):7200-7207. doi:, 10.1073/pnas.1914188117. Epub 2020 Mar 18. PMID:32188780 doi:http://dx.doi.org/10.1073/pnas.1914188117
- ↑ 5.0 5.1 According to Cai, Zhang et al. (their Fig. 4), the initial cut by furin occurs between Arg685 and Ser686 at * in the sequence PRRAR*SVASQ. Thus, S1 is 13-685 (length 673, excluding a 12 residue signal sequence), or 53% of the original chain, leaving S2 as 686-1273, length 588, 47%.
- ↑ Proteopedia's PyMOL morph server was used in both RigiMOL and linear modes, all atoms or only alpha carbon atoms. Rendering these as backbones or traces by Jmol gave broken lines. The reason for backbone breaking was not investigated further.
- ↑ BBEdit (barebones.com) has a regular expression "grep" mode that was used to delete unwanted lines. Deletion was done by find and replace with nothing. First, REMARK lines were deleted by finding ^REMARK.*\n, and similarly HETATM lines. Finally, non-CA ATOM lines were found with ^ATOM [ \d]\d\d\d\d [NCOS][ B-Z].*\n, leaving ATOM CA lines, MODEL and ENDMDL lines. This strategy was used after two other strategies failed. Selecting *.ca in the Jmol Java application and saving them produced a PDB file with numerous errors. I was unable to get regular expression alternation to work in either macOS Darwin sed, or GNU sed, thus unable to extract the desired 3 line types with "sed -n /match1|match2|match3/p". I was also unable to get BBEdit to delete lines not containing a specified string, e.g. find (?!MODEL).
