Glycogen Synthase Kinase-3 Interaction Domain Enhances Phosphorylation of SARS-CoV-2 Nucleocapsid Protein.
Mol Cells
; 45(12): 911-922, 2022 Dec 31.
Article
in English
| MEDLINE | ID: covidwho-2203932
ABSTRACT
A structural protein of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), nucleocapsid (N) protein is phosphorylated by glycogen synthase kinase (GSK)-3 on the serine/arginine (SR) rich motif located in disordered regions. Although phosphorylation by GSK-3ß constitutes a critical event for viral replication, the molecular mechanism underlying N phosphorylation is not well understood. In this study, we found the putative alpha-helix L/FxxxL/AxxRL motif known as the GSK-3 interacting domain (GID), found in many endogenous GSK-3ß binding proteins, such as Axins, FRATs, WWOX, and GSKIP. Indeed, N interacts with GSK-3ß similarly to Axin, and Leu to Glu substitution of the GID abolished the interaction, with loss of N phosphorylation. The N phosphorylation is also required for its structural loading in a virus-like particle (VLP). Compared to other coronaviruses, N of Sarbecovirus lineage including bat RaTG13 harbors a CDK1-primed phosphorylation site and Gly-rich linker for enhanced phosphorylation by GSK-3ß. Furthermore, we found that the S202R mutant found in Delta and R203K/G204R mutant found in the Omicron variant allow increased abundance and hyper-phosphorylation of N. Our observations suggest that GID and mutations for increased phosphorylation in N may have contributed to the evolution of variants.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Nucleocapsid Proteins
/
Glycogen Synthase Kinase 3
/
SARS-CoV-2
Type of study:
Observational study
/
Prognostic study
Topics:
Variants
Limits:
Humans
Language:
English
Journal:
Mol Cells
Journal subject:
Molecular Biology
Year:
2022
Document Type:
Article
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