Mutations in epigenetic regulators such as the SET domain-containing methyltransferase NSD2 are of high interest among the research community nowadays. The involvement of this mutations in multiple diseases put them in the spotlight. Interestingly, the change of the glutamic acid residue in the position 1099 of the NSD2 SET domain for a lysine residue has been recurrently found in multiple myeloma patients. This mutation produces a hyperactive enzyme that hypermethylate the natural enzymatic substrate: the lysine in the position 36 of the basic tail of the histone 3 in the nucleosomal context. Apparently, this hyperactivation may be related to the disruption of a critical salt-bridge that stabilize an autoregulatory loop of the NSD2 catalytic site. However, despite the extensive research that have been done around this phenomenon, the molecular mechanism behind this hyperactivation still remains unknow. For this reason, in this study we addressed this matter from a structural point of view by evaluating the structure and dynamics of the protein in solution by high-resolution Nuclear Magnetic Resonance (NMR) spectroscopy and biophysical techniques. We found increased local segmental motions in us to ms timescale that induced protein flexibility that may correlate with gain-of-function of E1099K miss-sense mutation. Further functional studies with the native substrates in vitro and in vivo are needed to understand this observation.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/676514 |
| Date | 03 1900 |
| Creators | Hincapié-Otero, María Mercedes |
| Contributors | Jaremko, Lukasz, Biological and Environmental Science and Engineering (BESE) Division, Khashab, Niveen M., Liberale, Carlo |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | 2024-04-25, At the time of archiving, the student author of this thesis opted to temporarily restrict access to it. The full text of this thesis will become available to the public after the expiration of the embargo on 2024-04-25. |
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