PLoS Pathogens | |
LEDGF/p75 Proteins with Alternative Chromatin Tethers Are Functional HIV-1 Cofactors | |
Manuel Llano1  Jose A. Garcia-Rivera1  James H. Morrison2  Mary Peretz2  Dyana T. Saenz2  Anne M. Meehan2  Eric M. Poeschla2  | |
[1] Biological Sciences Department, University of Texas, El Paso, Texas, United States of America;Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America | |
关键词: Chromatin; HIV-1; Histones; Nucleosomes; Cofactors (biochemistry); RNA interference; DNA-binding proteins; Cell cycle; cell division; | |
DOI : 10.1371/journal.ppat.1000522 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single integrase binding domain (IBD) binds integrase, a complex N-terminal domain ensemble (NDE) interacts with unknown chromatin ligands. Whether integration requires chromatin tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of LEDGF/p75 has been elusive. Here we replaced the NDE with strongly divergent chromatin-binding modules. The chimeras rescued integrase tethering and HIV-1 integration in LEDGF/p75-deficient cells. Furthermore, chromatin ligands could reside inside or outside the nucleosome core, and could be protein or DNA. Remarkably, a short Kaposi's sarcoma virus peptide that binds the histone 2A/B dimer converted GFP-IBD from an integration blocker to an integration cofactor that rescues over two logs of infectivity. NDE mutants were corroborative. Chromatin tethering per se is a basic HIV-1 requirement and this rather than engagement of particular chromatin ligands is important for the LEDGF/p75 cofactor mechanism.
【 授权许可】
CC BY
【 预 览 】
Files | Size | Format | View |
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RO201902014539626ZK.pdf | 1672KB | download |