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1.G.18 The SARS-CoV Fusion Peptide in the Spike Glycoprotein Precursor (SARS-FP) Family

The severe acute respiratory syndrom (SARS) coronavirus (CoV) fusion peptide is within the spike glycoprotein precursor.  The fusion peptide is a C-terminal 19 aas peptide, in the spike glycoprotein precursor of 1255 aas (Apellániz et al. 2014). Members of this family have a central CDD/Pfam Spike_rec_bind domain and a large C-terminal Corona_S2 domain. 120 references have been published on this and related proteins as of 3/2020. Generally, a stretch of 20-25 amino acids located at the N-terminus of the fusion protein, known as a fusion peptide, plays a decisive role in the fusion process. The stalk model of membrane fusion postulated a common route of bilayer transformation for stalk, transmembrane contact, and pore formation, and the fusion peptide is believed to facilitate bilayer transformation to promote membrane fusion (Meher and Chakraborty 2021). Single-domain antibodies (nanobodies) bind tightly to Spike and neutralize SARS-Co/V-2 (Schoof et al. 2020; Xiang et al. 2020.

The coronavirus spike protein (S) forms the distinctive virion surface structures that are characteristic of this viral family, appearing in negatively stained electron microscopy as stems capped with spherical bulbs. These structures are essential for the initiation of infection through attachment of the virus to cellular receptors followed by fusion to host cell membranes (Ye et al. 2004). The S protein can also mediate the formation of syncytia in infected cells. It is a large type I (1 TMS) protein, and all except a short carboxy-terminal segment of S constitutes the ectodomain. For the prototype coronavirus mouse hepatitis virus (MHV), S protein assembly into virions is specified by the carboxy-terminal segment, which comprises the transmembrane domain and the endodomain. Ye et al. 2004 genetically dissected these domains in the MHV S protein to localize the determinants of S incorporation into virions. Assembly competence maps to the endodomain of S, which is sufficient to target the protein for incorporation into the virion. The charge-rich carboxy-terminal region of the endodomain plays a major role. The adjacent cysteine-rich region of the endodomain is critical for fusion.

Wrapp et al. 2020 determined a 3.5-Å-resolution cryo-EM structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. They also provided biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. They tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they did not have appreciable binding to 2019-nCoV S (Wrapp et al. 2020).

References associated with 1.G.18 family:

Apellaniz B., Huarte N., Largo E. and Nieva JL. (2014). The three lives of viral fusion peptides. Chem Phys Lipids. 181:40-55. 24704587
Cai, Y., J. Zhang, T. Xiao, H. Peng, S.M. Sterling, R.M. Walsh, Jr, S. Rawson, S. Rits-Volloch, and B. Chen. (2020). Distinct conformational states of SARS-CoV-2 spike protein. Science 369: 1586-1592. 32694201
Liao, Y., Q. Yuan, J. Torres, J.P. Tam, and D.X. Liu. (2006). Biochemical and functional characterization of the membrane association and membrane permeabilizing activity of the severe acute respiratory syndrome coronavirus envelope protein. Virology 349: 264-275. 16507314
Meher, G. and H. Chakraborty. (2021). The role of fusion peptides in depth-dependent membrane organization and dynamics in promoting membrane fusion. Chem Phys Lipids 234: 105025. 33301753
Petit, C.M., V.N. Chouljenko, A. Iyer, R. Colgrove, M. Farzan, D.M. Knipe, and K.G. Kousoulas. (2007). Palmitoylation of the cysteine-rich endodomain of the SARS-coronavirus spike glycoprotein is important for spike-mediated cell fusion. Virology 360: 264-274. 17134730
Schoof, M., B. Faust, R.A. Saunders, S. Sangwan, V. Rezelj, N. Hoppe, M. Boone, C.B. Billesbølle, C. Puchades, C.M. Azumaya, H.T. Kratochvil, M. Zimanyi, I. Deshpande, J. Liang, S. Dickinson, H.C. Nguyen, C.M. Chio, G.E. Merz, M.C. Thompson, D. Diwanji, K. Schaefer, A.A. Anand, N. Dobzinski, B.S. Zha, C.R. Simoneau, K. Leon, K.M. White, U.S. Chio, M. Gupta, M. Jin, F. Li, Y. Liu, K. Zhang, D. Bulkley, M. Sun, A.M. Smith, A.N. Rizo, F. Moss, A.F. Brilot, S. Pourmal, R. Trenker, T. Pospiech, S. Gupta, B. Barsi-Rhyne, V. Belyy, A.W. Barile-Hill, S. Nock, Y. Liu, N.J. Krogan, C.Y. Ralston, D.L. Swaney, A. García-Sastre, M. Ott, M. Vignuzzi, , P. Walter, and A. Manglik. (2020). An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science 370: 1473-1479. 33154106
Wrapp, D., N. Wang, K.S. Corbett, J.A. Goldsmith, C.L. Hsieh, O. Abiona, B.S. Graham, and J.S. McLellan. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367: 1260-1263. 32075877
Xiang, Y., S. Nambulli, Z. Xiao, H. Liu, Z. Sang, W.P. Duprex, D. Schneidman-Duhovny, C. Zhang, and Y. Shi. (2020). Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science 370: 1479-1484. 33154108
Ye, R., C. Montalto-Morrison, and P.S. Masters. (2004). Genetic analysis of determinants for spike glycoprotein assembly into murine coronavirus virions: distinct roles for charge-rich and cysteine-rich regions of the endodomain. J. Virol. 78: 9904-9917. 15331724