Structural studies of coronavirus fusion proteins

Seminar

Event Date: 

Tue, May 16, 2017

Time: 

4pm

Location: 

T-639

Speaker: 

Dr David Veesler

Host: 

Dr Joseph Mougous

Coronaviruses are enveloped viruses responsible for 30% of mild respiratory infections and atypical pneumonia in humans worldwide. The emergence of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 demonstrated these zoonotic viruses can transmit to humans from various animal species and suggested that additional emergence events are likely to occur. The fatality rate of SARS-CoV and MERS-CoV infections are about 10-37% and there are no approved antiviral treatments or vaccines against human coronaviruses.

Entry of coronaviruses into cells is mediated by the trimeric transmembrane spike glycoprotein, which carries receptor-binding and membrane fusion functions. It also contains the principal antigenic determinants and is the target of neutralizing antibodies during infection. Coronavirus spike glycoproteins had proven reluctant to structural characterization using traditional approaches since these proteins are metastable, heavily glycosylated and feature numerous disulfide bonds. My lab determined the first high-resolution structure of a coronavirus spike glycoprotein trimer using cryoEM and single particle image reconstruction techniques. Our structure revealed that coronavirus spike and paramyxovirus F proteins share a common core, implicating mechanistic similarities and an evolutionary connection between these viral fusion proteins. Comparisons with crystal structures of human coronavirus spike domains allowed rationalization of the molecular basis for species specificity based on the use of spatially contiguous but distinct domains. The outcome of this study indicated potential vaccinology strategies to elicit broadly neutralizing antibodies against coronaviruses.

We also recently determined an atomic resolution reconstruction of the spike glycoprotein trimer of HCoV-NL63, which is an α-coronavirus that can cause severe lower-respiratory-tract infections requiring hospitalization. The significant resolution improvement as compared with earlier studies revealed the presence of an extended glycan shield obstructing the protein surface and provided a structural framework to understand accessibility to neutralizing antibodies. Finally, our results suggested that HCoV-NL63 and other coronaviruses use molecular trickery, based on epitope masking with glycans and activating conformational changes, to evade the immune system of infected hosts, in a manner similar to that described for HIV-1.