Molecular architecture and conservation of an immature human endogenous retrovirus

Anna-Sophia Krebs, Hsuan-Fu Liu, Ye Zhou, Juan S. Rey, Lev Levintov, Juan Shen, Andrew Howe, Juan R. Perilla (), Alberto Bartesaghi () and Peijun Zhang ()
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Anna-Sophia Krebs: Wellcome Trust Centre for Human Genetics, University of Oxford
Hsuan-Fu Liu: Duke University School of Medicine
Ye Zhou: Duke University
Juan S. Rey: University of Delaware
Lev Levintov: University of Delaware
Juan Shen: Wellcome Trust Centre for Human Genetics, University of Oxford
Andrew Howe: Diamond Light Source, Harwell Science and Innovation Campus
Juan R. Perilla: University of Delaware
Alberto Bartesaghi: Duke University School of Medicine
Peijun Zhang: Wellcome Trust Centre for Human Genetics, University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging. The structure shows a hexamer unit oligomerized through a 6-helix bundle, which is stabilized by a small molecule analogous to IP6 in immature HIV-1 capsid. The HERV-K immature lattice is assembled via highly conserved dimer and trimer interfaces, as detailed through all-atom molecular dynamics simulations and supported by mutational studies. A large conformational change mediated by the linker between the N-terminal and the C-terminal domains of CA occurs during HERV-K maturation. Comparison between HERV-K and other retroviral immature capsid structures reveals a highly conserved mechanism for the assembly and maturation of retroviruses across genera and evolutionary time.

Date: 2023
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DOI: 10.1038/s41467-023-40786-w

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