Investigation of the Biochemical Interaction Between GFI1/1B and LSD1 in the Presence of LSD1 Inhibition
CitationSu, Cindy. 2020. Investigation of the Biochemical Interaction Between GFI1/1B and LSD1 in the Presence of LSD1 Inhibition. Master's thesis, Harvard Extension School.
AbstractAcute Myeloid Leukemia (AML) is a form of leukemia characterized by the proliferation of undifferentiated white blood cells. Although there are many contributing factors that lead to AML, situations regarding the overexpression of essential epigenetic regulators is correlated to poor prognosis in AML patients. In some cases, a histone demethylase, Lysine Specific Demethylase 1, LSD1, is overexpressed, thereby leading to the development of inhibitors against the protein. This is evidenced by the plethora of reversible and irreversible compounds synthesized by pharmaceutical companies over the past few years, including an irreversible inhibitor, GSK-LSD1, that is currently in clinical trials. The inhibition of LSD1 abrogates cell proliferation. GSK-LSD1 inhibits LSD1 in a suicide-inactivation mechanism through a covalent modification in the catalytic pocket, resulting in cell the abrogation of cell proliferation. Initially, it was hypothesized that GSK-LSD1causes cell death by diminishing LSD1 catalytic activity. But it was recently discovered that GSK-LSD1 disrupts protein-protein interactions between LSD1 and GFI1/1B. This discovery, therefore, suggests that LSD1 catalytic activity is not essential for leukemia proliferation, rather it is the maintenance in protein interaction between LSD1 and GFI1/1B that allows for cell proliferation.
This finding is an example of why it is important to understand the molecular and biochemical basis of this protein interaction – investigating this interaction allows researchers to improve and alter small-molecule drugs for clinical use. For instance, in a disease state where mutations in LSD1 may arise in the catalytic pocket, perhaps the mutations provide a loss of enzyme activity phenotype but is able to maintain the interaction between GFI1/1B. Since drug binding occurs in the catalytic pocket, the drug may no longer bind in the mutated pocket, so the protein interaction is sustained and a drug resistant mutant arises due to the drug’s inability to disrupt the protein interaction. Although some research has been done to understand LSD1-GFI1B interaction in physiological state, little is known about the interaction between other domains of LSD1 and alternate regions of GFI1B that allow for this interaction, since peripheral domains may allow for allosteric interaction and regulation of downstream effects. Thus, it would be of importance to further study this interaction as it may allow researchers to identify additional drug-able sites on LSD1 or GFI1B.
Based on past literature, the SNAG domain is known to act as a molecular hook for LSD1 with SNAI1, but this domain is expressed in other SNAG containing proteins, including GFI1/1B. Research has shown that mutation of the phenylalanine at the 5 position of the SNAG domain in SNAI1 prevents interaction between LSD1. As such, using sequence conservation between SNAI1 and GFI1B in the SNAG domain, we hypothesize that binding of GSK-LSD1 perturbs this interaction through a bumping mechanism in the phenylalanine position of the SNAG domain in GFI1/1B. The data obtained from this research can elucidate the types of drugs that can be effective LSD1 inhibitors to block LSD1 and GFI1/1B interaction.
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