Conformational Dynamics in the Interaction of SARS-CoV-2 Papain-like Protease with Human Interferon-Stimulated Gene 15 Protein
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Published on: January 9, 2019
Wellington C Leite1, Kevin L Weiss1, Gwyndalyn Phillips1
1Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States.
Abstract:
Papain-like protease (PLpro) from SARS-CoV-2 plays essential roles in the replication cycle of the virus. In particular, it preferentially interacts with and cleaves human interferon-stimulated gene 15 (hISG15) to suppress the innate immune response of the host. We used small-angle X-ray and neutron scattering combined with computational techniques to study the mechanism of interaction of SARS-CoV-2 PLpro with hISG15. We showed that hISG15 undergoes a transition from an extended to a compact state after binding to PLpro, a conformation that has not been previously observed in complexes of SARS-CoV-2 PLpro with ISG15 from other species. Furthermore, computational analysis showed significant conformational flexibility in the ISG15 N-terminal domain, suggesting that it is weakly bound to PLpro and supports a binding mechanism that is dominated by the C-terminal ISG15 domain. This study fundamentally improves our understanding of the SARS-CoV-2 deISGylation complex that will help guide development of COVID-19 therapeutics targeting this complex.
Insights
SARS-CoV-2 papain-like protease (PLpro) interacts with human interferon-stimulated gene 15 (hISG15), altering its structure to suppress the immune response. This reveals a novel binding mechanism crucial for developing COVID-19 therapeutics.
Area of Science:
- Structural biology
- Virology
- Immunology
Background:
- SARS-CoV-2 papain-like protease (PLpro) is vital for viral replication.
- PLpro suppresses host innate immunity by cleaving human interferon-stimulated gene 15 (hISG15).
Purpose of the Study:
- To elucidate the interaction mechanism between SARS-CoV-2 PLpro and hISG15.
- To understand the structural changes in hISG15 upon binding to PLpro.
Main Methods:
- Small-angle X-ray scattering (SAXS)
- Small-angle neutron scattering (SANS)
- Computational modeling
Main Results:
- hISG15 transitions from an extended to a compact state when bound to SARS-CoV-2 PLpro.
- This compact conformation of hISG15 is unique compared to other species' ISG15-PLpro complexes.
- Computational analysis indicates weak binding of the hISG15 N-terminal domain and dominant binding by the C-terminal domain.
Conclusions:
- The study provides fundamental insights into the SARS-CoV-2 deISGylation complex.
- Findings guide the development of novel COVID-19 therapeutics targeting the PLpro-hISG15 interaction.
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