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Preparation and characterization of human cellular cofactors of retroviral integration.
Čermáková, Kateřina ; Maloy Řezáčová, Pavlína (advisor) ; Obšil, Tomáš (referee)
Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a prominent cellular binding partner of Human Immunodeficiency Virus type 1 (HIV-1) integrase. It is a human nuclear protein, which has been implicated in transcriptional regulation and cell survival. The role of LEDGF/p75 in HIV integration is well characterized, the HIV integrase binding domain (IBD) was identified and structural studies, which provide detail information about this interaction, were done. However, very little is known about its physiological function. As a transcriptional co-activator, LEDGF/p75 is implicated not only in HIV replication, but also in human cancer and autoimmunity. Key feature for both, the viral and cellular role of this protein, is its ability to act as a molecular adaptor tethering proteins to the chromatin fiber. Recently, PogZ (Pogo transposable element derived protein with zinc finger domain) was identified and validated as a new cellular interaction partner of LEDGF/p75. It was shown, that their interaction is mediated by IBD of LEDGF/p75 and the C-terminal domain of PogZ. To gain more insight in this interaction, we have initiated structural studies of their complex. Structural information is crucial for understanding the LEDGF/p75 biological role and might help in design of inhibitors selectively blocking...
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Detailed characterization of the interaction between LEDGF/p75 and MeCP2
Naušová, Karolína ; Veverka, Václav (advisor) ; Hrabal, Richard (referee)
Epigenetics investigates heritable phenotype changes that are not caused by alternations in DNA sequence. Major epigenetic mechanisms include covalent DNA modifications (particularly methylation), histone and chromatin modifications and RNA interference. These mechanisms are involved in number of processes from transcription to translation. Lens epithelium-derived growth factor (LEDGF/p75) is ubiquitously expressed in human body and it is considered to be a transcriptional coactivator upregulated upon stress conditions. LEDGF/p75 consists of several domains. The N-terminal PWWP domain plays very important role from epigenetic point of view as it is able to bind di- and trimethylated lysine 36 of histone 3, which is considered as an epigenetic marker of transcriptionally active chromatin. LEDGF/p75 interaction partners include e.g. HIV integrase, MLL1-MENIN complex or MeCP2. A shorter isoform of LEDGF/p75 called LEDGF/p52 shares with LEDGF/p75 its N- terminal part that is responsible for interaction with DNA and chromatin. Methyl-CpG-binding protein 2 (MeCP2) is present everywhere in human body with the highest abundance in brain. MeCP2 is a transcriptional modulator remodelling chromatin, therefore its function is to activate or repress gene depending on the molecular and cellular context. Among...
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Preparation and characterization of human cellular cofactors of retroviral integration.
Čermáková, Kateřina ; Maloy Řezáčová, Pavlína (advisor) ; Obšil, Tomáš (referee)
Lens epithelium-derived growth factor/p75 (LEDGF/p75) is a prominent cellular binding partner of Human Immunodeficiency Virus type 1 (HIV-1) integrase. It is a human nuclear protein, which has been implicated in transcriptional regulation and cell survival. The role of LEDGF/p75 in HIV integration is well characterized, the HIV integrase binding domain (IBD) was identified and structural studies, which provide detail information about this interaction, were done. However, very little is known about its physiological function. As a transcriptional co-activator, LEDGF/p75 is implicated not only in HIV replication, but also in human cancer and autoimmunity. Key feature for both, the viral and cellular role of this protein, is its ability to act as a molecular adaptor tethering proteins to the chromatin fiber. Recently, PogZ (Pogo transposable element derived protein with zinc finger domain) was identified and validated as a new cellular interaction partner of LEDGF/p75. It was shown, that their interaction is mediated by IBD of LEDGF/p75 and the C-terminal domain of PogZ. To gain more insight in this interaction, we have initiated structural studies of their complex. Structural information is crucial for understanding the LEDGF/p75 biological role and might help in design of inhibitors selectively blocking...
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