Publication Date:
2015-06-11
Description:
Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/-3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530500/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maskell, Daniel P -- Renault, Ludovic -- Serrao, Erik -- Lesbats, Paul -- Matadeen, Rishi -- Hare, Stephen -- Lindemann, Dirk -- Engelman, Alan N -- Costa, Alessandro -- Cherepanov, Peter -- P50 GM082251-06/GM/NIGMS NIH HHS/ -- R01 AI070042/AI/NIAID NIH HHS/ -- R01 AI070042-08/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):366-9. doi: 10.1038/nature14495. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] National Institute for Biological Standards and Control, Microscopy and Imaging, Blanche Lane, South Mimms EN6 3QG, UK. ; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; NeCEN, Gorlaeus Laboratory, Einsteinweg 55, Leiden, 2333, the Netherlands. ; Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK. ; Institute of Virology, Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. ; Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061770" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Substitution
;
Binding Sites/genetics
;
Cryoelectron Microscopy
;
DNA/genetics/metabolism/ultrastructure
;
Genome/genetics
;
Histones/chemistry/metabolism/ultrastructure
;
Integrases/metabolism
;
Models, Molecular
;
Nucleosomes/*chemistry/genetics/ultrastructure/*virology
;
Protein Multimerization
;
Recombination, Genetic
;
Spumavirus/chemistry/genetics/*metabolism/ultrastructure
;
*Virus Integration
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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