The type I glycoprotein S of Coronavirus, trimers of which constitute the typical viral spikes, is assembled into virions through noncovalent interactions with the M protein. The spike glycoprotein is translated as a large polypeptide that is subsequently cleaved to S1 and S2 [[cite:PUB00003124]]. The cleavage of S can occur at two distinct sites: S2 or S2' [[cite:PUB00093087]]. The S1 subunit is responsible for host-receptor binding while the S2 subunit contains the membrane-fusion machinery [[cite:PUB00094056]].
\nBoth chimeric S proteins appeared to cause cell fusion when expressed individually, suggesting that they were biologically fully active [[cite:PUB00006464]]. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail [[cite:PUB00006522]].
","llm":false,"checked":false,"updated":false},{"text":"The S2 subunit normally contains multiple key components, including one or more fusion peptides (FP), a second proteolytic site (S2') and two conserved heptad repeats (HRs), driving membrane penetration and virus-cell fusion. The HRs can trimerize into a coiled-coil structure built of three HR1-HR2 helical hairpins presenting as a canonical six-helix bundle and drag the virus envelope and the host cell bilayer into close proximity, preparing for fusion to occur [[cite:PUB00094063]]. The fusion core is composed of HR1 and HR2 and at least three membranotropic regions that are denoted as the fusion peptide (FP), internal fusion peptide (IFP), and pretransmembrane domain (PTM). The HR regions are further flanked by the three membranotropic components. Both FP and IFP are located upstream of HR1, while PTM is distally downstream of HR2 and directly precedes the transmembrane domain of SARS-CoV S. All of these three components are able to partition into the phospholipid bilayer to disturb membrane integrity. [[cite:PUB00094063]]. During the pandemic, many conservative amino acid changes in FP segment of SARS-CoV-2 have been reported (i.e., L821I, L822F, K825R, V826L, T827I, L828P, A829T, D830G/A, A831V/S/T, G832C/S, F833S, I834T), although their impact is not known as the active conformation and mode of insertion of SARS-CoV-2 fusion peptide have not been experimentally characterised. Differences in HR1 sequences between SARS-CoV and SARS-CoV-2 suggest that SARS-CoV-2 HR2 makes stronger interactions with HR1. However, the substitutions observed in the solvent accessible surface of the HR1 domain (e.g., D936Y, S943P, S939F) of SARS-CoV-2 do not seem to be involved in stabilizing interactions with HR2. Substitutions in HR2 (e.g., K1073N, V1176F) or the TM or cytoplasmic tail domains have also been observed, but further experimental work is required to determine the effects of these changes [[cite:PUB00099876]].
","llm":false,"checked":false,"updated":false}],"wikipedia":null,"literature":{"PUB00094063":{"PMID":26206723,"ISBN":null,"volume":"23","issue":"8","year":2015,"title":"Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond.","URL":null,"raw_pages":"468-78","medline_journal":"Trends Microbiol","ISO_journal":"Trends Microbiol.","authors":["Lu G","Wang Q","Gao GF."],"DOI_URL":null},"PUB00093087":{"PMID":19321428,"ISBN":null,"volume":"106","issue":"14","year":2009,"title":"Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites.","URL":null,"raw_pages":"5871-6","medline_journal":"Proc Natl Acad Sci U S A","ISO_journal":"Proc. Natl. Acad. Sci. U.S.A.","authors":["Belouzard S","Chu VC","Whittaker GR."],"DOI_URL":null},"PUB00099876":{"PMID":34580920,"ISBN":null,"volume":null,"issue":null,"year":2021,"title":"Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic.","URL":null,"raw_pages":null,"medline_journal":"Proteins","ISO_journal":"Proteins","authors":["Lubin JH","Zardecki C","Dolan EM","Lu C","Shen Z","Dutta S","Westbrook JD","Hudson BP","Goodsell DS","Williams JK","Voigt M","Sarma V","Xie L","Venkatachalam T","Arnold S","Alfaro Alvarado LH","Catalfano K","Khan A","McCarthy E","Staggers S","Tinsley B","Trudeau A","Singh J","Whitmore L","Zheng H","Benedek M","Currier J","Dresel M","Duvvuru A","Dyszel B","Fingar E","Hennen EM","Kirsch M","Khan AA","Labrie-Cleary C","Laporte S","Lenkeit E","Martin K","Orellana M","Ortiz-Alvarez de la Campa M","Paredes I","Wheeler B","Rupert A","Sam A","See K","Soto Zapata S","Craig PA","Hall BL","Jiang J","Koeppe JR","Mills SA","Pikaart MJ","Roberts R","Bromberg Y","Hoyer JS","Duffy S","Tischfield J","Ruiz FX","Arnold E","Baum J","Sandberg J","Brannigan G","Khare SD","Burley SK."],"DOI_URL":null},"PUB00003124":{"PMID":2984314,"ISBN":null,"volume":"66 ( Pt 4)","issue":null,"year":1985,"title":"Cloning and sequencing of the gene encoding the spike protein of the coronavirus IBV.","URL":null,"raw_pages":"719-26","medline_journal":"J Gen Virol","ISO_journal":"J. Gen. Virol.","authors":["Binns MM","Boursnell ME","Cavanagh D","Pappin DJ","Brown TD."],"DOI_URL":null},"PUB00094056":{"PMID":30356097,"ISBN":null,"volume":"8","issue":"1","year":2018,"title":"Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis.","URL":null,"raw_pages":"15701","medline_journal":"Sci Rep","ISO_journal":"Sci Rep","authors":["Kirchdoerfer RN","Wang N","Pallesen J","Wrapp D","Turner HL","Cottrell CA","Corbett KS","Graham BS","McLellan JS","Ward AB."],"DOI_URL":null},"PUB00006522":{"PMID":10725213,"ISBN":null,"volume":"269","issue":"1","year":2000,"title":"Coronavirus-induced membrane fusion requires the cysteine-rich domain in the spike protein.","URL":null,"raw_pages":"212-24","medline_journal":"Virology","ISO_journal":"Virology","authors":["Chang KW","Sheng Y","Gombold JL."],"DOI_URL":"http://dx.doi.org/10.1006/viro.2000.0219"},"PUB00006464":{"PMID":10627571,"ISBN":null,"volume":"74","issue":"3","year":2000,"title":"Assembly of spikes into coronavirus particles is mediated by the carboxy-terminal domain of the spike protein.","URL":null,"raw_pages":"1566-71","medline_journal":"J Virol","ISO_journal":"J. Virol.","authors":["Godeke GJ","de Haan CA","Rossen JW","Vennema H","Rottier PJ."],"DOI_URL":"http://dx.doi.org/10.1128/JVI.74.3.1566-1571.2000"}},"set_info":null,"overlaps_with":[{"accession":"IPR044873","name":"Spike glycoprotein S2, coronavirus, heptad repeat 1","type":"domain"},{"accession":"IPR002552","name":"Spike glycoprotein S2, coronavirus","type":"domain"},{"accession":"IPR044874","name":"Spike glycoprotein S2, coronavirus, heptad repeat 2","type":"domain"}],"counters":{"subfamilies":0,"domain_architectures":0,"interactions":0,"matches":13935,"pathways":11,"proteins":7607,"proteomes":235,"sets":0,"structural_models":{"alphafold":182,"bfvd":32},"structures":1567,"taxa":1417},"entry_annotations":{},"cross_references":{},"is_llm":false,"is_reviewed_llm":false,"is_updated_llm":false,"representative_structure":{"accession":"2bez","name":"Structure of a proteolitically resistant core from the severe acute respiratory syndrome coronavirus S2 fusion protein"}}}