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Generation and Assembly of Virus-Specific Nucleocapsids of the Respiratory Syncytial Virus
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A small loop in the capsid protein of Moloney murine leukemia virus controls assembly of spherical cores

Marcy R Auerbach1, Kristy R Brown, Artem Kaplan

  • 1Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032, USA.

Journal of Virology
|February 28, 2006
PubMed

Insights

Researchers discovered a new domain in Moloney murine leukemia virus (MoLV) Gag protein crucial for spherical core formation. Mutations in this capsid protein (CA) loop block viral assembly and release, suggesting a potential therapeutic target for retroviral diseases.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • Moloney murine leukemia virus (MoLV) is a retrovirus that requires proper assembly of its Gag polyprotein into spherical cores for viral release.
  • The capsid protein (CA) of retroviruses plays a critical role in viral assembly and core formation.
  • Understanding the structural determinants of MoLV Gag assembly is essential for developing antiviral strategies.

Purpose of the Study:

  • To identify novel domains within the MoLV Gag protein important for spherical core formation.
  • To investigate the role of the N-terminal domain of the MoLV capsid protein (CA) in viral assembly and release.
  • To explore the potential of identified regions as therapeutic targets for retroviral diseases.

Main Methods:

  • Analysis of 18 insertional mutations in the N-terminal domain of MoLV CA.
  • Transmission electron microscopy (TEM) to visualize viral assembly in mutant-producing cells.
  • X-ray crystallography to determine the structure of the hexameric form of MLV CA.

Main Results:

  • Three insertional mutations severely impaired viral assembly and release, leading to Gag protein accumulation in flat patches at the plasma membrane.
  • Mutations localized to a small loop between alpha-helices 4 and 5 of CA, analogous to the cyclophilin A-binding loop in HIV-1 CA.
  • TEM and structural analysis suggest these mutations disrupt the transition from planar Gag lattices to spherical cores, potentially by interfering with pentamer formation or pentamer-hexamer interactions.

Conclusions:

  • A novel domain in the MoLV CA N-terminal domain, specifically a loop between alpha-helices 4 and 5, is critical for spherical core formation and viral release.
  • Mutations in this loop prevent the proper curvature and closure of the viral core, despite allowing initial Gag lattice formation.
  • This CA loop represents a potential novel therapeutic target for controlling retroviral infections.

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