Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 434, Issue 9, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2022.167516
Keywords
ras GTPase-activating protein-binding protein 1; SARS-CoV-2 nucleocapsid protein; stress granule; NTF2-like domain; pathogen-host interaction
Categories
Funding
- NIH [1R21AI147057, R35GM119721, R01AI153419]
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The interaction between the nucleocapsid (N) protein of SARS-CoV-2 and G3BP1 plays a crucial role in suppressing stress granule formation and promoting viral production. This study provides insights into the molecular basis of the interaction and its potential implications for developing therapeutic strategies against SARS-CoV-2 infection.
Stress granule (SG) formation mediated by Ras GTPase-activating protein-binding protein 1 (G3BP1) constitutes a key obstacle for viral replication, which makes G3BP1 a frequent target for viruses. For instance, the SARS-CoV-2 nucleocapsid (N) protein interacts with G3BP1 directly to suppress SG assembly and promote viral production. However, the molecular basis for the SARS-CoV-2 N -G3BP1 interaction remains elusive. Here we report biochemical and structural analyses of the SARS-CoV-2 N -G3BP1 interaction, revealing differential contributions of various regions of SARS-CoV-2 N to G3BP1 binding. The crystal structure of the NTF2-like domain of G3BP1 (G3BP1(NTF2)) in complex with a peptide derived from SARS-CoV-2 N (residues 1-25, N1-25) reveals that SARS-CoV-2 N1-25 occupies a conserved surface groove of G3BP1(NTF2) via surface complementarity. We show that a phi-x-F (phi, hydrophobic residue) motif constitutes the primary determinant for G3BP1(NTF2)-targeting proteins, while the flanking sequence underpins diverse secondary interactions. We demonstrate that mutation of key interaction residues of the SARS-CoV-2 N1-25 -G3BP1(NTF2) complex leads to disruption of the SARS-CoV-2 N -G3BP1 interaction in vitro. Together, these results provide a molecular basis of the strain-specific interaction between SARS-CoV-2 N and G3BP1, which has important implications for the development of novel therapeutic strategies against SARS-CoV-2 infection. (C)& nbsp;2022 Elsevier Ltd. All rights reserved.
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