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KMID : 0578320220450120911
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Molecules and Cells
2022 Volume.45 No. 12 p.911 ~ p.922
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Glycogen Synthase Kinase-3 Interaction Domain Enhances Phosphorylation of SARS-CoV-2 Nucleocapsid Protein
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Yun Jun-Seop
Song Hye-Eun
Kim Nam-Hee
Cha So-Young
Hwang Kyu-Ho
Lee Jae-Eun
Jeong Cheol-Hee
Song Sang-Hyun
Kim Seong-Hun
Cho Eunae Sandra
Kim Hyun-Sil
Yook Jong-In
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Abstract
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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-3β 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-3β binding proteins, such as Axins, FRATs, WWOX, and GSKIP. Indeed, N interacts with GSK-3β 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-3β. 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.
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KEYWORD
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Axin, Delta and Omicron variants, glycogen synthase kinase-3, nucleocapsid, phosphorylation, severe acute respiratory syndrome coronavirus 2
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