Wednesday, April 24, 2024
4/24/2024
¿ DESCRIPTION (provided by applicant): Glutamylation is the isopeptide addition of one or more glutamate residues onto a backbone glutamate of a protein. This unique post-translational modification (PTM) was fortuitously discovered to occur on the acidic stretches of tubulin in 1990. More recently it was discovered that many other proteins within the cell are subject to glutamylation. Many of these other proteins fall into the category of nuclear proteins and histone chaperones. In the same study, the authors identified the enzyme tubulin tyrosine ligase-like 4 (TTLL4) as the main glutamyltransferase responsible for non-tubulin substrates. While the role of glutamylation on tubulin has been studied, there remains no published data addressing the role of glutamylation of nuclear proteins within the cell. The overall objective of this study is t understand the role of histone chaperone glutamylation in regulating histone binding and deposition. We have previously shown that the histone chaperone Nucleoplasmin (Npm2) is subject to glutamylation during Xenopus laevis embryogenesis. We have localized this modification to 4 glutamate residues within the second acidic patch on the intrinsically disordered C-terminal tail domain of Npm. We have previously shown that this region is critical for efficient histone binding and deposition and likely makes direct contacts with histones. Given this information we hypothesize that glutamylation of the histone chaperone Nucleoplasmin leads to an increase in affinity toward histones and a decrease in its ability to deposit histones onto DNA. If successful this study will be the first to probe the role of glutamylation of a non-tubulin substrate. The findings of this work will be broadly applicable due to the extreme conservation of acidic patches on histone chaperones and the observation that other histone chaperones are glutamylated in vivo.
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