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].

     N-term.  S1

   1 MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHSTQDLFLPFFSS1

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

     ---------- ---------- ---------- ---------- ---------- ----------
 181 GKQGNFKNLR EFVFKNIDGY FKIYSKHTPI NLVRDLPQGF SALEPLVDLP IGINITRFQT
     ---------- ---------- ---------- ---------- -V-------- ----------
                                                 20A.EU1
 241 LLALHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK
     ---------- ---------- ---------- ---------- ---------- ----------

 301 CTLKSFTVEK GIYQTSNFRVQPTESIVRFP NITNLCPFGEVFNATRFASVYAWNRKRISNRBD

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

 361 CVADYSVLYNSASFSTFKCY GVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIAD

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

 421 YNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPC
     ---------- ----SR--KK ---RFV---- -RF--L-R-- ---------- QV---SNIS-
                                                                20A.EU2
     ---------- ---------- -----S---- -----E-Q-- ---------- ------R---
     ---------- ---------- ---------- ---------- ---------- ------I---
                     ACE2 BINDING
 481 NGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHA PATVCGPKKS TNLVKNKCVN
     DSA-SS---S ---P----R- --F-C--H-APA-------- ---------- ----------
     --I------- ---------- ---------SRS-------- ---------- ----------

Reference

Antiviral Peptides SARS-CoVs

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

Du L, He Y, Zhou Y, et al. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nature reviews. Microbiology. 2009 Mar;7(3):226-236. [PMC]

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; Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. bioRxiv 2020.04.29.069054. [pdf]

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]

---...---