Structural basis for functional tetramerization of lentiviral integrase.
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 domai...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-07-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC2705190?pdf=render |
| _version_ | 1819030824945713152 |
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| author | Stephen Hare Francesca Di Nunzio Alfred Labeja Jimin Wang Alan Engelman Peter Cherepanov |
| author_facet | Stephen Hare Francesca Di Nunzio Alfred Labeja Jimin Wang Alan Engelman Peter Cherepanov |
| author_sort | Stephen Hare |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T06:36:18Z |
| format | Article |
| id | doaj.art-b57452ab680d4d43bf92a1f264e5cdd4 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-21T06:36:18Z |
| publishDate | 2009-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-b57452ab680d4d43bf92a1f264e5cdd42022-12-21T19:12:51ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742009-07-0157e100051510.1371/journal.ppat.1000515Structural basis for functional tetramerization of lentiviral integrase.Stephen HareFrancesca Di NunzioAlfred LabejaJimin WangAlan EngelmanPeter CherepanovExperimental 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.http://europepmc.org/articles/PMC2705190?pdf=render |
| spellingShingle | Stephen Hare Francesca Di Nunzio Alfred Labeja Jimin Wang Alan Engelman Peter Cherepanov Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathogens |
| title | Structural basis for functional tetramerization of lentiviral integrase. |
| title_full | Structural basis for functional tetramerization of lentiviral integrase. |
| title_fullStr | Structural basis for functional tetramerization of lentiviral integrase. |
| title_full_unstemmed | Structural basis for functional tetramerization of lentiviral integrase. |
| title_short | Structural basis for functional tetramerization of lentiviral integrase. |
| title_sort | structural basis for functional tetramerization of lentiviral integrase |
| url | http://europepmc.org/articles/PMC2705190?pdf=render |
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