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Publications

Journal Article Epublish

PubMed: 40341088 DOI: 10.1038/s41467-025-59402-0

Saddle curvature association of nsP1 facilitates the replication complex assembly of Chikungunya virus in cells.

Nat Commun 16(1):4282

Authors: Xinwen Miao, Michelle Cheok Yien Law, Jatin Kumar, Choon-Peng Chng, Yongpeng Zeng, Yaw Bia Tan, Jiawei Wu, Xiangfu Guo, Lizhen Huang, Yinyin Zhuang, Weibo Gao, Changjin Huang, Dahai Luo, Wenting Zhao

Affiliations

  • School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
  • Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
  • School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.
  • School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore. State Key Laboratory Breeding Base of Green Chemistry Synthesis Technology, College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, China.
  • School of Electrical & Electronic Engineering, Nanyang Technological University, Singapore, Singapore. School of Physics and Mathematical Science, Nanyang Technological University, Singapore, Singapore.
  • School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore.
  • Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
  • NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore.
  • National Centre for Infectious Diseases, Singapore, Singapore.
  • School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
  • Institute for Digital Molecular Analytics and Science, Nanyang Technological University, Singapore, Singapore.

Abstract

Positive-sense RNA viruses, including SARS-CoV-1 and -2, DENV, and CHIKV, replicate in curved membrane compartments within host cells. Non-structural proteins (nsPs) critically regulate these nanoscale membrane structures, yet their curvature-dependent assembly remains elusive due to the challenges of imaging nanoscale interaction on curved surfaces. Using vertically aligned nanostructures to generate pre-defined membrane curvatures, we here investigate the impact of curvature on nsPs assembly. Taking CHIKV as a model, we reveal that nsP1 preferentially binds and stabilizes on positively curved membranes, with stronger accumulation at radii ≤150 nm. This is driven by hydrophobic residues in the membrane association (MA) loops of individual nsP1. Molecular dynamics simulations further confirm the improved binding stability of nsP1 on curved membranes, particularly when it forms a dodecamer ring. Together, nsP1 supports a strong saddle curvature association, with flexible MA loops sensing a range of positive curvatures in the x-z plane while the rigid dodecamer stabilizing fixed negative curvature in the x-y plane - crucial for constraining the membrane spherule neck during replication progression. Moreover, CHIKV replication enriches on patterned nanoring structures, underscoring the curvature-guided assembly of the viral replication complex. Our findings highlight membrane curvature as a key regulator of viral nsPs organization, opening new avenues for studying membrane remodeling in viral replication.

MeSH

Cells, Biological Science Disciplines, Virus Replication, Chikungunya Virus, Viruses, Positive-Strand Rna Viruses, Membranes