RAPID: Molecular Insights into the SARS-CoV-2 Spike Protein Activation via a Novel Interaction with a Human Cell Surface Target Protein

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, single-stranded RNA virus that belongs to the subgenus sarbecvirus of Coronaviridae. Members of the Coronaviridae family include the SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV), which are the responsible human pathogens for the common cold and other emerging severe respiratory conditions. SARS-CoV and SARS-CoV-2 attach to the host cells by binding to the angiotensin converting enzyme 2 (ACE2) receptor. Viral entry is facilitated by the binding of the receptor binding domain (RBD) of the coronavirus spike protein to the ACE2 receptor. However, SARS-CoV-2 targets type II alveolar cells in the lung that have relatively low ACE2 expression compared to ACE2 expression in other organs. Thus, other co-receptors have been identified that are targeted by the virus and which likely provide for an alternative entry point for the virus. While SARS-CoV-2 infects fewer organs compared to SARS-CoV, the mechanisms remain inconclusive. This research project will provide structural insights into the novel role of a human cell surface protein in SARS-CoV-2 entry and replication. There is an urgent need for gaining insight into this possible second entry point for the virus into cells. Additionally, this project includes an educational outreach component geared towards the underrepresented minorities and in particular the younger population, an incredibly important sub popular who might be underestimating the impact of SARS.

This research project will use the first 300 kV cryo Atomic Resolution Microscope (ARM), installed to date in the US, to determine the near atomic resolution structures of the novel interaction between a human cell surface protein and the SARS-CoV-2 spike protein. Biochemical assays will additionally validate the structural findings. Thus, significant mechanistic insights into viral pathogenesis will be published rapidly from data obtained on a new cryo-electron microscope in the US that has aided near atomic resolution insights into many biological processes from several laboratories overseas, including from Europe and Asia. By determining the mechanistic insights into how SARS-CoV-2 infects fewer organs compared to SARS-CoV, the findings obtained in this research project could explain the lower mortality of SARS-CoV-2 compared to SARS-CoV. Collectively, the structural insights into the mechanism of the interaction of the SARS-CoV-2 spike protein with a human cell surface protein will: (i) further the understanding on how COVID-19 is spreading, (ii) shed light onto some of the key differences of SARS-CoV-2 versus SARS-CoV, and (iii) provide mechanistic insights into the higher transmissibility of SARS-CoV-2. Such virus-host study will contribute to a broader understanding of viral pathogenesis.

This RAPID award is made by the Cellular Dynamics and Functionl Program in the Division of Molecular and Cellular Biosciences, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.