Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

Michał S Barski; Jordan J Minnell; Zuzana Hodakova; Valerie E Pye; Andrea Nans; Peter Cherepanov; Goedele N Maertens

doi:10.1038/s41467-020-18874-y

Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

Nat Commun. 2020 Oct 7;11(1):5043. doi: 10.1038/s41467-020-18874-y.

Authors

Michał S Barski¹, Jordan J Minnell¹, Zuzana Hodakova², Valerie E Pye², Andrea Nans³, Peter Cherepanov^{1

2}, Goedele N Maertens⁴

Affiliations

¹ Imperial College London, St Mary's Hospital, Department of Infectious Disease, Section of Virology, Norfolk Place, London, W2 1PG, UK.
² Chromatin Structure and Mobile DNA Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
³ Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
⁴ Imperial College London, St Mary's Hospital, Department of Infectious Disease, Section of Virology, Norfolk Place, London, W2 1PG, UK. [email protected].

Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs / genetics
Cloning, Molecular
Cryoelectron Microscopy
Crystallography, X-Ray
DNA, Viral / metabolism
DNA, Viral / ultrastructure
Human T-lymphotropic virus 1 / enzymology
Human T-lymphotropic virus 1 / genetics
Human T-lymphotropic virus 1 / pathogenicity*
Humans
Integrases / genetics
Integrases / metabolism
Integrases / ultrastructure*
Leukemia-Lymphoma, Adult T-Cell / pathology
Leukemia-Lymphoma, Adult T-Cell / virology
Molecular Docking Simulation
Mutagenesis, Site-Directed
Paraparesis, Tropical Spastic / pathology
Paraparesis, Tropical Spastic / virology
Protein Multimerization
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism
Protein Phosphatase 2 / ultrastructure*
Protein Structure, Quaternary
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Recombinant Proteins / ultrastructure
Sequence Homology, Amino Acid
Simian T-lymphotropic virus 1 / enzymology*
Simian T-lymphotropic virus 1 / genetics
Single Molecule Imaging
Viral Proteins / genetics
Viral Proteins / metabolism
Viral Proteins / ultrastructure*
Virus Integration*

Substances

DNA, Viral
Recombinant Proteins
Viral Proteins
Integrases
PPP2R5C protein, human
Protein Phosphatase 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding