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Force boosts SARS-CoV-2 invasion

Cell Res. (2021)

SARS-CoV-2 invades host cells by using its spike protein to recognize host receptors such as ACE2. A recent study suggests that the mechanical force generated host plasma membrane bending enhances ACE2-dependent SARS-CoV-2 invasion.

The spike protein has S1 and S2 subunits. The S1 subunit contains the receptor-binding domain (RBD) for initial ACE2 recognition; the S2 subunit forms the fusion machinery after S1 and S2 dissociation. Using single-molecule biophysical assays and molecular dynamics simulation, Hu and colleagues found that increasing mechanical force by up to 10 pN prolonged the SARS-CoV-2-RBD association with ACE2 and accelerated S1 and S2 dissociation. Force strengthened SARS binding to ACE2 to a weaker extent, which might explain its reduced contagiousness compared with SARS-CoV-2. A more infectious SARS-CoV-2 spike variant, D614G, showed stronger ACE2 binding and faster S1 and S2 dissociation under force stimulation compared with wild-type spike protein. Two RBD mutations that impair force-dependent RBD–ACE2 binding compromised pseudovirus infection. The results suggest that force-activated spike–ACE2 recognition facilitates SARS-CoV-2 infection. A SARS-CoV-2-neutralizing, S1/S2-targeting antibody derived from convalescent patients with COVID-19 was shown to impede force-accelerated S1 and S2 detachment.

This study adds mechanical force as a regulator of SARS-CoV-2 host cell entry.

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Correspondence to Jie Wang.

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Wang, J. Force boosts SARS-CoV-2 invasion. Nat Cell Biol 23, 1051 (2021).

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