Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • HHMI Damon Runyon Postdoctoral Fellow in Jesse Bloom's lab, Fred Hutchinson Cancer Research Center
    Biography

      Dr. Tyler Starr is an HHMI Damon Runyon Postdoctoral Fellow in Jesse Bloom’s lab at the Fred Hutchinson Cancer Research Center in Seattle, Washington. He researches the molecular evolution of viral and immune genes, combining computational evolutionary analyses with high-throughput experimental assays to characterize the effects of amino-acid mutations on protein function. These experiments highlight biochemical constraints on protein function, inform the design of vaccines and antibody therapeutics, and illuminate the evolutionary forces that shape key viral and immune proteins.


    Abstract

    The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. Our data will inform vaccine design and functional annotation of mutations observed during viral surveillance, and motivate future directions in molecular evolution and immunology of SARS-related coronaviruses.

    Learning Objectives:

    1. Define deep mutational scanning and its use in understanding protein function and evolution

    2. Interpret patterns of mutational tolerance in light of SARS-CoV-2 functional and antigenic evolution

    3. Describe patterns of circulating genetic variation in SARS-CoV-2


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