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J. Biol. Chem., Vol. 280, Issue 33, 29588-29595, August 19, 2005

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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^*

From the ^aDepartment of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing 100871, the ^cBioinformation Center/institute of Plant Physiology and Ecology/Health Science Center, Shanghai institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, the ^dState Key Laboratory for Medical Genomics/Pôle Sino-Francais de Recherche en Sciences du Vivant et Génomique, Ruijin Hospital Affiliated with the Shanghai Second Medical University, Shanghai 200025, the ^eChinese National Human Genome Center, 250 Bi Bo Road, Zhang Jiang High Tech Park, Shanghai 201203, the ^fState Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, and the ^gState Key Laboratory of Genetic Engineering/Department of Microbiology, School of Life Science, Fudan University, Shanghai 200433, China

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.

Received for publication, January 19, 2005 , and in revised form, June 16, 2005.

^* This work was supported by the National Nature Science Foundation of China (Grant 30340027), by the Ministry of Science and Technology (Grant 2003CB514116), by the National Nature Science Foundation of China (Outstanding Young Scientist Award 30125022 (to H.-K. D.), by the Ministry of Science and Technology (Grant G1999011904 to M.-X. D.), and by a special grant for the "Animal Reservoir of SARS-CoV" from the Ministry of Science and Technology of China, and the Sixth Framework Program "EPISARS" from the European Commission, a P2R Project of Chinese-French Research Collaboration Network on SARS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b These authors contributed equally to this work.

^h To whom correspondence may be addressed. Tel.: 86-21-5080-1919; Fax: 86-21-5080-1922; E-mail: gpzhao{at}sibs.ac.cn. iTo whom correspondence may be addressed. Tel.: 86-10-6275-6954; Fax: 86-10-6275-6954; E-mail: hongkui_deng{at}pku.edu.cn.

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