Abstract
Human papillomavirus (HPV) is a significant health burden and leading cause of virus-induced cancers. However, studies have been hampered due to restricted tropism that makes production and purification of high titer virus problematic. This issue has been overcome by developing alternative HPV production methods such as virus-like particles (VLPs), which are devoid of a native viral genome. Structural studies have been limited in resolution due to the heterogeneity, fragility, and stability of the VLP capsids. The mouse papillomavirus (MmuPV1) presented here has provided the opportunity to study a native papillomavirus in the context of a common laboratory animal. Using cryo EM to solve the structure of MmuPV1, we achieved 3.3 Å resolution with a local symmetry refinement method that defined smaller, symmetry related subparticles. The resulting high-resolution structure allowed us to build the MmuPV1 asymmetric unit for the first time and identify putative L2 density. We also used our program ISECC to quantify capsid flexibility, which revealed that capsomers move as rigid bodies connected by flexible linkers. The MmuPV1 flexibility was comparable to that of a HPV VLP previously characterized. The resulting MmuPV1 structure is a promising step forward in the study of papillomavirus and will provide a framework for continuing biochemical, genetic, and biophysical research for papillomaviruses.
Highlights
In 2011, a mouse papillomavirus was identified in a colony of nude (NMRI-Foxn1nu /Foxn1nu ) mice in India and later named as Mus musculus papillomavirus 1 (MmuPV1) [1]. there are other identified rodent papillomaviruses, this was the first rodent papillomavirus that was found to infect laboratory strains of mice [2]
Virus particles containing internal density were selected for a reconstruction with icosahedral symmetry imposed, which resulted in a 4.4 Å resolution map
Reconstructions of papillomaviruses with full icosahedral symmetry imposed have produced maps limited to modest resolution; recently subparticle reconstruction approaches have been successfully used to obtain high resolution [16,17,36]
Summary
In 2011, a mouse papillomavirus was identified in a colony of nude (NMRI-Foxn1nu /Foxn1nu ) mice in India and later named as Mus musculus papillomavirus 1 (MmuPV1) [1]. there are other identified rodent papillomaviruses, this was the first rodent papillomavirus that was found to infect laboratory strains of mice [2]. In 2011, a mouse papillomavirus was identified in a colony of nude Foxn1nu ) mice in India and later named as Mus musculus papillomavirus 1 (MmuPV1) [1]. There are other identified rodent papillomaviruses, this was the first rodent papillomavirus that was found to infect laboratory strains of mice [2]. The capsid is composed of 72 capsomers, each containing five copies of L1, the major capsid protein. Each capsid contains an undetermined number of L2, the minor capsid protein. There are 12 pentavalent capsomers per virus particle that have true 5-fold symmetry since they are surrounded by 5 neighboring capsomers. There are 60 hexavalent capsomers per virus particle that have pseudo 6-fold symmetry, indicating that each is surrounded by 6 neighboring capsomers that are not evenly spaced. For each copy of L1 a loop of the C-terminus forms a connecting arm by extending to a neighboring capsomer, forming a stabilizing disulfide bond, and returning to the donating capsomer
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