Receptor Binding Domains and Coronavirus Adaptation and Evolution

Coronaviruses are enveloped RNA viruses that cause respiratory diseases in humans and other animals. The continued circulation of human coronaviruses and the large reservoir of non-human coronaviruses that have the potential to infect humans represent a significant health concern. Similar to other RNA viruses, coronaviruses are characterized by a high mutation rate, and evolution and adaptation has accompanied the diversification of coronaviruses. The coronavirus spike protein is a viral membrane protein involved in host receptor binding and fusion of the viral and host cell membranes. Reported here is work performed on the spike proteins of two human common cold causing coronaviruses: HCoV-229E and HCoV-OC43. Specifically, the X-ray crystal structures of the following were determined: i) the receptor binding domain (RBD) of the S-protein of HCoV-229E in complex with human aminopeptidase N (hAPN) and ii) the carbohydrate binding domain (CBD) of the S-protein of HCoV-OC43 in complex with 9-O-Acetyl-N-acetylneuraminic acid (Neu5,9Ac2). In addition, viral sequence analysis, binding studies, and comparative sequence and structural analysis among closely related coronaviruses were performed. The observation that the greatest variability shown by natural viral isolates of HCoV-229E is located in the receptor binding loops is quite surprising from a receptor binding standpoint. However, this observation suggests that the receptor binding region is changing due to viral selection. Indeed, our results indicate that the optimization of receptor binding affinity and/or immune evasion, two known determinants of viral fitness, are operative in the emergence of new viral isolates. Although less well characterized at this point, natural viral sequence variation at or near the carbohydrate binding site of HCoV-OC43 is also observed, an indication that similar selection pressures are operative. Together, our results provide mechanistic insights into coronavirus adaptation and evolution.

Department dc:contributor.department

Biochemistry

Year dc:date.issued

2018

Author dc:creator

• Wong, Alan

Advisor dc:contributor.advisor

• Rini, James

Handle dc:identifier.uri

http://hdl.handle.net/1807/101670

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/101670