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Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome.

Published on Jan 6, 2017in Science41.063
· DOI :10.1126/science.aah5163
D.O. Passos4
Estimated H-index: 4
(Salk Institute for Biological Studies),
Min Li10
Estimated H-index: 10
(NIH: National Institutes of Health)
+ 7 AuthorsDmitry Lyumkis19
Estimated H-index: 19
(Salk Institute for Biological Studies)
Abstract
Like all retroviruses, HIV-1 irreversibly inserts a viral DNA (vDNA) copy of its RNA genome into host target DNA (tDNA). The intasome, a higher-order nucleoprotein complex composed of viral integrase (IN) and the ends of linear vDNA, mediates integration. Productive integration into host chromatin results in the formation of the strand transfer complex (STC) containing catalytically joined vDNA and tDNA. HIV-1 intasomes have been refractory to high-resolution structural studies. We used a soluble IN fusion protein to facilitate structural studies, through which we present a high-resolution cryo–electron microscopy (cryo-EM) structure of the core tetrameric HIV-1 STC and a higher-order form that adopts carboxyl-terminal domain rearrangements. The distinct STC structures highlight how HIV-1 can use the common retroviral intasome core architecture to accommodate different IN domain modules for assembly.
  • References (56)
  • Citations (55)
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References56
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Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo–electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previousl...
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The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retrovira...
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An unexpected octameric integrase architecture for the betaretrovirus mouse mammary tumour virus intasome.
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A crystal structure of the octameric integrase from Rous sarcoma virus in complex with viral and target DNAs.
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Background Retroviral integration favors weakly conserved palindrome sequences at the sites of viral DNA joining and generates a short (4–6 bp) duplication of host DNA flanking the provirus. We previously determined two key parameters that underlie the target DNA preference for prototype foamy virus (PFV) and human immunodeficiency virus type 1 (HIV-1) integration: flexible pyrimidine (Y)/purine (R) dinucleotide steps at the centers of the integration sites, and base contacts with specific integ...
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