Identification of two critical amino acid residues of the severe acute respiratory syndrome coronavirus spike protein for its variation in zoonotic tropism transition via a double substitution strategy

Xiu Xia Qu, Pei Hao, Xi Jun Song, Si Ming Jiang, Yan Xia Liu, Pei Gang Wang, Xi Rao, Huai Dong Song, Sheng Yue Wang, Yu Zuo, Ai Hua Zheng, Min Luo, Hua Lin Wang, Fei Deng, Han Zhong Wang, Zhi Hong Hu, Ming Xiao Ding, Guo Ping Zhao, Hong Kui Deng

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a recently identified human coronavirus. The extremely high homology of the viral genomic sequences between the viruses isolated from human (huSARS-CoV) and those of palm civet origin (pcSARS-CoV) suggested possible palm civet-to-human transmission. Genetic analysis revealed that the spike (S) protein of pcSARS-CoV and huSARS-CoV was subjected to the strongest positive selection pressure during transmission, and there were six amino acid residues within the receptor-binding domain of the S protein being potentially important for SARS progression and tropism. Using the single-round infection assay, we found that a two-amino acid substitution (N479K/T487S) of a huSARS-CoV for those of pcSARS-CoV almost abolished its infection of human cells expressing the SARS-CoV receptor ACE2 but no effect upon the infection of mouse ACE2 cells. Although single substitution of these two residues had no effects on the infectivity of huSARS-CoV, these recombinant S proteins bound to human ACE2 with different levels of reduced affinity, and the two-amino acid-substituted S protein showed extremely low affinity. On the contrary, substitution of these two amino acid residues of pcSARS-CoV for those of huSRAS-CoV made pcSARS-CoV capable of infecting human ACE2-expressing cells. These results suggest that amino acid residues at position 479 and 487 of the S protein are important determinants for SARS-CoV tropism and animal-to-human transmission.

Original languageEnglish (US)
Pages (from-to)29588-29595
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number33
DOIs
StatePublished - Aug 19 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Qu, X. X., Hao, P., Song, X. J., Jiang, S. M., Liu, Y. X., Wang, P. G., Rao, X., Song, H. D., Wang, S. Y., Zuo, Y., Zheng, A. H., Luo, M., Wang, H. L., Deng, F., Wang, H. Z., Hu, Z. H., Ding, M. X., Zhao, G. P., & Deng, H. K. (2005). Identification of two critical amino acid residues of the severe acute respiratory syndrome coronavirus spike protein for its variation in zoonotic tropism transition via a double substitution strategy. Journal of Biological Chemistry, 280(33), 29588-29595. https://doi.org/10.1074/jbc.M500662200