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Structural Basis for Functional Tetramerization of Lentiviral Integrase
DOI:
10.1371/journal.ppat.1000515
PMID:
19609359
Authors:
Stephen
Hare
(Imperial College London)
,
Francesca
Di Nunzio
(Dana-Farber Cancer Institute, Boston)
,
Alfred
Labeja
(Imperial College London)
,
Jimin
Wang
(Yale University)
,
Alan
Engelmann
(Dana-Farber Cancer Institute, Boston)
,
Peter
Cherepanov
(Imperial College London)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Plos Pathogens
, VOL 5(7)
State:
Published (Approved)
Published:
July 2009

Abstract: Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor
Journal Keywords: X-Ray; HIV; HIV-1; Integrases; Intercellular; Models; Molecular; Mutation; Protein; Viral; Visna-maedi; vpr; Human Immunodeficiency Virus
Subject Areas:
Biology and Bio-materials
Instruments:
I02-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Added On:
08/09/2009 16:11
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