Identifying primate ACE2 variants that confer resistance to SARS-CoV-2
SARS-CoV-2 infects humans through the binding of viral S-protein (spike protein) to human ACE2 (angiotensin I converting enzyme 2). There are 27 ACE2 amino acid residues that bind to S-protein. From human sequence databases, we identified 9 ACE2 variants at ACE2-S-protein binding sites. We used both experimental assays and protein structure analysis to evaluate the effect of each variant on the binding affinity of ACE2 to S-protein. We found that all 9 variants change the binding affinity of ACE2 to S-protein: six of them reduce the binding affinity significantly or even completely while the other three increase the binding affinity form 50 to 100%. We then collected the ACE2 gene sequences from 57 non-human primates. Among the six apes and 20 Old World monkeys (OWMs) studied we found no new variants. In contrast, all 11 New World monkeys (NWMs) studied share four variants each causing a strong reduction in binding affinity and the Philippine tarsier also possesses three such variants. Moreover, 18 of the 19 prosimian species studied share one variant causing a strong reduction in binding affinity. Based on these findings we proposed that the common ancestor of primates was strongly resistant to and that of NWMs was completely resistant to SARS-CoV-2 and so is the Philippine tarsier, whereas apes and OWMs, like most humans, are susceptible. This study was published in Molecular Biology and Evolution, one of the best journals in molecular evolution (IF=16.24). The collaborative team includes the labs of Dr. Lily Wang of National Tsing Hua University, Dr. Yan Yuan Tseng of Wayne State University and Dr. Wen-Hsiung Li of Academia Sinica.
The paper can be read online at:
Maloyjo Joyraj Bhattacharjee, Jinn-Jy Lin, Chih-Yao Chang, Yu-Ting Chiou, Tian-Neng Li, Chia-Wei Tai, Tz-Fan Shiu, Chi-An Chen, Chia-Yi Chou, Paromita Chakraborty, Yan Yuan Tseng*, Lily Hui-Ching Wang*, Wen-Hsiung Li*(2021)Identifying Primate ACE2 Variants That Confer Resistance to SARS-CoV-2. Molecular Biology and Evolution, 38(7): 2715–2731