The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function

0583040 - ÚOCHB 2025 RIV CH eng J - Článek v odborném periodiku
Brouns, T. - Lux, Vanda - Van Belle, S. - Christ, F. - Veverka, Václav - Debyser, Z.
The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function.
Cells. Roč. 13, č. 3 (2024), č. článku 227. E-ISSN 2073-4409
Grant CEP: GA ČR(CZ) GA22-03028S; GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: DNA-binding protein * protein-DNA interaction * protein-protein interaction * chromatin structure * protein dynamic * LEDGF/p75 * DNA-induced protein binding
Impakt faktor: 6, rok: 2022
Způsob publikování: Open access
https://doi.org/10.3390/cells13030227

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 alpha 6-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 alpha 6-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.
Trvalý link: https://hdl.handle.net/11104/0351072