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Nucleic Acids Res. 2014 Aug;42(14):9096-107. doi: 10.1093/nar/gku634. Epub 2014 Jul 22.

Major capsid reinforcement by a minor protein in herpesviruses and phage.

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Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Department of Medicinal Chemistry, University of Washington School of Pharmacy, H172 Health Sciences Building, Box 357610, Seattle, WA 98195, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Department of Physics, Carnegie Mellon University, Pittsburgh, PA 15213, USA Department of Biochemistry and Structural Biology, Lund University, Box 124, Lund, Sweden


Herpes simplex type 1 virus (HSV-1) and bacteriophage λ capsids undergo considerable structural changes during self-assembly and DNA packaging. The initial steps of viral capsid self-assembly require weak, non-covalent interactions between the capsid subunits to ensure free energy minimization and error-free assembly. In the final stages of DNA packaging, however, the internal genome pressure dramatically increases, requiring significant capsid strength to withstand high internal genome pressures of tens of atmospheres. Our data reveal that the loosely formed capsid structure is reinforced post-assembly by the minor capsid protein UL25 in HSV-1 and gpD in bacteriophage λ. Using atomic force microscopy nano-indentation analysis, we show that the capsid becomes stiffer upon binding of UL25 and gpD due to increased structural stability. At the same time the force required to break the capsid increases by ∼70% for both herpes and phage. This demonstrates a universal and evolutionarily conserved function of the minor capsid protein: facilitating the retention of the pressurized viral genome in the capsid. Since all eight human herpesviruses have UL25 orthologs, this discovery offers new opportunities to interfere with herpes replication by disrupting the precise force balance between the encapsidated DNA and the capsid proteins crucial for viral replication.

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