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Mutations in the SARS-CoV-2 Spike Protein

The spike (S) protein of the virus mediates receptor binding and membrane fusion. The sequence specificity also defines the range of the hosts and the specificity of the virus. Also, the S protein is the target for a variety of neutralizing antibodies and vaccine design.

Gene recombination or mutations of the receptor-binding domain (RBD) appears to allow transmission between different hosts. Some of these mutations can lead to a higher mortality rate of the infected hosts. Some observed mutations are in the reference sequence for the spike protein. Korber et al. developed a analysis pipeline to track mutations in the SARS-CoV-2 spike protein. However, the clinical evidence of all these mutations still needs to be verified.

Schematic of the coronavirus spike (S) protein domain structure


The location of receptor-binding subunit S1, the membrane-fusion subunit S2, the transmembrane anchor (TM), the intercellular tail (IC) are indicated. The location of the S1 N-terminal domain (S1-NTD), the S1 C-terminal domain (S1-CTD), the fusion peptide (FP), and the heptade repeat regions N and C (HR-N and HR-C) are indicated as well.

The following image shows the annotated sequence for SARS-CoV-2 spike protein mutations from the coronavirus associated with COVID-19 originating in Wuhan of Hubei province in China. Source: ORIGIN   YP_009724390, 1273 a, surface glycoprotein [Severe acute respiratory syndrome coronavirus 2].

A new SARS-CoV-2 virus emerged in the UK containing a noval set of spike mutations named B.1.1.7. This new virus strain appears to be more infectious.

The potential biological effects of these mutations are:

(i)  Mutation N501Y is part of six key contact residues within the receptor-binding domain (RBD) thought to increase binding
     affinity to human and murine receptor protein ACE2.

(ii)  The spike deletion 69-70del may help the virus to evade the human immune response.

(iii)  Mutation P681H is close to the furin cleavage site.

Other identified mutations in B.1.1.7 spike protein are: A570D, T716I, S982A, D1118H.


     N-termS1

   1 MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS S1

     ---------- ---------- ---------- ---------- ---------- ---------- 
  61 NVTWFHAIHV SGTNGTKRFD NPVLPFNDGV YFASTEKSNI IRGWIFGTTL DSKTQSLLIV
     --------|| ---------Y ---------- -------F-- ---------- ----------
          B.1.1.7 Del S:D80Y               S:S98F
 121 NNATNVVIKV CEFQFCNDPF LGVYYHKNNK SWMESEFRVY SSANNCTFEY VSQPFLMDLE

     ---------- ---------- ---|------ ---------- ---------- ----------
                      B.1.1.7 Deletion

 181 GKQGNFKNLR EFVFKNIDGY FKIYSKHTPI NLVRDLPQGF SALEPLVDLP IGINITRFQT
     ---------- ---------- ---------- ---------- -V-------- ----------
                                                
20A.EU1

 241
LLALHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK
     ---------- ---------- ---------- ---------- ---------- ----------

 301 CTLKSFTVEK GIYQTSNFRV QPTESIVRFP NITNLCPFGE VFNATRFASV YAWNRKRISN RBD

     ---------- ---------- ---------- ------SL-- IL-S---S-- -S-D----N-

 361 CVADYSVLYN SASFSTFKCY GVSPTKLNDL CFTNVYADSF VIRGDEVRQI APGQTGKIAD

     ------F--S -T----LN-- ---LA----- --P-I----- ----VQ-IE- ---R--N---
     ---------- -S-----R-- ---------- ---------- ---------- ---E------
     ---------- ---------- ---------- ---------- ---------- ---A------

 421 YNYKLPDDFT GCVIAWNSNN LDSKVGGNYN YLYRLFRKSN LKPFERDIST EIYQAGSTPC
     ---------- ----SR--KK ---RFV---- -RF--L-R-- ---------- QV---SNIS-
                                                                20A.EU2
     ---------- ---------- -----S---- -----E-Q-- ---------- ------R---
     ---------- ---------- ---------- ---------- ---------- ------I---
                     ACE2 BINDING
 481 NGVEGFNCYF PLQSYGFQPT NGVGYQPYRV VVLSFELLHA PATVCGPKKS TNLVKNKCVN
     DSA-SS---S ---P----R- --F-C--H-A PA-------- ---------- ----------
     --I------- ---------- Y--------S RS-------- ---------- ----------

                        B.1.1.7

 541 FNFNGLTGTG VLTESNKKFL PFQQFGRDIA DTTDAVRDPQ TLEILDITPC SFGGVSVITP
     ---------- ---------- ---------D ---------- ---------- ----------
                                 B.1.1.7
 601 GTNTSNQVAV LYQDVNCTEV PVAIHADQLT PTWRVYSTGS NVFQTRAGCL IGAEHVNNSY
     ---------- ---G------ ---------- ---------- ---------- ---------- 
                 D614G        FURIN 1         2
     .......................<-S1|S2->.....<-|->.........................
 661 ECDIPIGAGI CASYQTQTNS PRRAR|SVASQ SIIAY|TMSLG AENSVAYSNN SIAIPTNFTI
     ---------- ---------- H-A-A ----- ----- ----- ---------- -----I----
                        B.1.1.7                                 B.1.1.7

 721 SVTTEILPVS MTKTSVDCTM YICGDSTECS NLLLQYGSFC TQLNRALTGI AVEQDKNTQE
     ---------- ---------- ---------- ---------- ---------- ----------
                                              S2’
     ........INTERNAL FUSION PEPTIDE......<-|->.....FUSION PEPTIDE.....
 781 VFAQVKQIYK TPPIKDFGGF NFSQILPDPS KPSKRS|FIED LLFNKVTLAD AGFIKQYGDC
     ---------- ---------- ---------- ------ P--- ---------- ----------

 841 LGDIAARDLI CAQKFNGLTV LPPLLTDEMI AQYTSALLAG TITSGWTFGA GAALQIPFAM
     ---------- ---------- ---------- ---------- ---------- -P------P-

 901 QMAYRFNGIG VTQNVLYENQ KLIANQFNSA IGKIQDSLSS TASALGKLQD VVNQNAQALN HR1
     ---------- ---------- ---------- ---------- -P-------- ----------

 961 TLVKQLSSNF GAISSVLNDI LSRLDKVEAE VQIDRLITGR LQSLQTYVTQ QLIRAAEIRA
     ---------- ---------- -A---PP--- ---------- ---------- ----------
                         B.1.1.7
1021 SANLAATKMS ECVLGQSKRV DFCGKGYHLM SFPQSAPHGV VFLHVTYVPA QEKNFTTAPA
     ---------- ---------- ---------- ---------- ---------- ----------

1081 ICHDGKAHFP REGVFVSNGT HWFVTQRNFY EPQIITTDNT FVSGNCDVVI GIVNNTVYDP
     ---------- ---------- ---------- -------H-- ---------- ----------
                                          B.1.1.7
1141 LQPELDSFKE ELDKYFKNHT SPDVDLGDIS GINASVVNIQ KEIDRLNEVA KNLNESLIDL HR2

1201 QELGKYEQYI KWPWYIWLGF IAGLIAIVMV TIMLCCMTSC CSCLKGCCSC GSCCKFDEDD CPD

1261 SEPVLKGVKL
HYT


Reference

Antiviral Peptides SARS-CoVs

B.1.1.7 : Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations
Report written by: Andrew Rambaut, Nick Loman, Oliver Pybus, Wendy Barclay, Jeff Barrett, Alesandro Carabelli, Tom Connor, Tom Peacock, David L Robertson, Erik Volz, on behalf of COVID-19 Genomics Consortium UK (CoG-UK).

Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020 Apr;176:104742. [PMC]

Coronavirus Genomes

COVID Vaccine Peptides

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Emma B. Hodcroft, Moira Zuber, Sarah Nadeau, Iñaki Comas, Fernando González Candelas, SeqCOVID-SPAIN consortium, Tanja Stadler, Richard A. Neher; Emergence and spread of a SARS-CoV-2 variant through Europe in the summer of 2020. medRxiv 2020.10.25.20219063.
 
Isabel, S., Graña-Miraglia, L., Gutierrez, J.M. et al. Evolutionary and structural analyses of SARS-CoV-2 D614G spike protein mutation now documented worldwide. Sci Rep 10, 14031 (2020). [pdf]

B Korber, WM Fischer, S Gnanakaran, H Yoon, J Theiler, W Abfalterer, B Foley, EE Giorgi, T Bhattacharya, MD Parker, DG Partridge, CM Evans, TM Freeman, TI de Silva, on behalf of the Sheffield COVID-19 Genomics Group, CC LaBranche, DC Montefiori;
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Lai AL, Millet JK, Daniel S, Freed JH, Whittaker GR. The SARS-CoV Fusion Peptide Forms an Extended Bipartite Fusion Platform that Perturbs Membrane Order in a Calcium-Dependent Manner. J Mol Biol. 2017 Dec 8;429(24):3875-3892. [PMC]

Shen S, Tan TH, Tan YJ. Expression, glycosylation, and modification of the spike (S) glycoprotein of SARS CoV. Methods Mol Biol. 2007;379:127-35. [PMC]

Structure and sequence of SARS-CoV-2

Tang T, Bidon M, Jaimes JA, Whittaker GR, Daniel S. Coronavirus membrane fusion mechanism offers a potential target for antiviral development. Antiviral Res. 2020 Jun;178:104792. doi: 10.1016/j.antiviral.2020.104792. [PMC]

Therapeutic Peptides

Therapeutic strageties for vaccination

Xiao X, Dimitrov DS. The SARS-CoV S glycoprotein. Cell Mol Life Sci. 2004 Oct;61(19-20):2428-30. [PMC]



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