The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function
The transcriptional co-activator lens epithelium-derived growth factor/p75 (LEDGF/p75) plays an important role in the biology of the cell and in several human diseases, including MLL-rearranged acute leukemia, autoimmunity, and HIV-1 infection. In both health and disease, LEDGF/p75 functions as a ch...
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MDPI AG
2024-01-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/3/227 |
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| author | Tine Brouns Vanda Lux Siska Van Belle Frauke Christ Václav Veverka Zeger Debyser |
| author_facet | Tine Brouns Vanda Lux Siska Van Belle Frauke Christ Václav Veverka Zeger Debyser |
| author_sort | Tine Brouns |
| collection | DOAJ |
| description | The transcriptional co-activator lens epithelium-derived growth factor/p75 (LEDGF/p75) plays an important role in the biology of the cell and in several human diseases, including MLL-rearranged acute leukemia, autoimmunity, and HIV-1 infection. In both health and disease, LEDGF/p75 functions as a chromatin tether that interacts with proteins such as MLL1 and HIV-1 integrase via its integrase-binding domain (IBD) and with chromatin through its N-terminal PWWP domain. Recently, dimerization of LEDGF/p75 was shown, mediated by a network of electrostatic contacts between amino acids from the IBD and the C-terminal α<sub>6</sub>-helix. Here, we investigated the functional impact of LEDGF/p75 variants on the dimerization using biochemical and cellular interaction assays. The data demonstrate that the C-terminal α<sub>6</sub>-helix folds back in cis on the IBD of monomeric LEDGF/p75. We discovered that the presence of DNA stimulates LEDGF/p75 dimerization. LEDGF/p75 dimerization enhances binding to MLL1 but not to HIV-1 integrase, a finding that was observed in vitro and validated in cell culture. Whereas HIV-1 replication was not dependent on LEDGF/p75 dimerization, colony formation of MLLr-dependent human leukemic THP-1 cells was. In conclusion, our data indicate that intricate changes in the quaternary structure of LEDGF/p75 modulate its tethering function. |
| first_indexed | 2024-03-08T03:59:32Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T03:59:32Z |
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| series | Cells |
| spelling | doaj.art-5f1ec83871864e7ab48c3460f74818d42024-02-09T15:09:38ZengMDPI AGCells2073-44092024-01-0113322710.3390/cells13030227The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering FunctionTine Brouns0Vanda Lux1Siska Van Belle2Frauke Christ3Václav Veverka4Zeger Debyser5Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, BelgiumInstitute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague, Czech RepublicLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, BelgiumLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, BelgiumInstitute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 16000 Prague, Czech RepublicLaboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Flanders, BelgiumThe transcriptional co-activator lens epithelium-derived growth factor/p75 (LEDGF/p75) plays an important role in the biology of the cell and in several human diseases, including MLL-rearranged acute leukemia, autoimmunity, and HIV-1 infection. In both health and disease, LEDGF/p75 functions as a chromatin tether that interacts with proteins such as MLL1 and HIV-1 integrase via its integrase-binding domain (IBD) and with chromatin through its N-terminal PWWP domain. Recently, dimerization of LEDGF/p75 was shown, mediated by a network of electrostatic contacts between amino acids from the IBD and the C-terminal α<sub>6</sub>-helix. Here, we investigated the functional impact of LEDGF/p75 variants on the dimerization using biochemical and cellular interaction assays. The data demonstrate that the C-terminal α<sub>6</sub>-helix folds back in cis on the IBD of monomeric LEDGF/p75. We discovered that the presence of DNA stimulates LEDGF/p75 dimerization. LEDGF/p75 dimerization enhances binding to MLL1 but not to HIV-1 integrase, a finding that was observed in vitro and validated in cell culture. Whereas HIV-1 replication was not dependent on LEDGF/p75 dimerization, colony formation of MLLr-dependent human leukemic THP-1 cells was. In conclusion, our data indicate that intricate changes in the quaternary structure of LEDGF/p75 modulate its tethering function.https://www.mdpi.com/2073-4409/13/3/227DNA-binding proteinprotein–DNA interactionprotein–protein interactionchromatin structureprotein dynamicLEDGF/p75 |
| spellingShingle | Tine Brouns Vanda Lux Siska Van Belle Frauke Christ Václav Veverka Zeger Debyser The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function Cells DNA-binding protein protein–DNA interaction protein–protein interaction chromatin structure protein dynamic LEDGF/p75 |
| title | The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function |
| title_full | The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function |
| title_fullStr | The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function |
| title_full_unstemmed | The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function |
| title_short | The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function |
| title_sort | impact of lens epithelium derived growth factor p75 dimerization on its tethering function |
| topic | DNA-binding protein protein–DNA interaction protein–protein interaction chromatin structure protein dynamic LEDGF/p75 |
| url | https://www.mdpi.com/2073-4409/13/3/227 |
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