Evading the guardian of the genome: a biophysical study on p53 mutations

Ortiz Martínez, Cèlia

Evading the guardian of the genome: a biophysical study on p53 mutations

Citació

Ortiz Martínez, C. Evading the guardian of the genome: a biophysical study on p53 mutations. 2023. handle: http://hdl.handle.net/10230/56871

Aquesta citació s'ha generat automàticament.

Resum

p53, the most frequently mutated protein in human cancers, is a tumor-suppressor in charge of regulating gene expression when there is DNA damage to prevent the cell from becoming cancerous. p53 can only carry out this regulatory function when found in the proper structural form consisting of an aggregate of four identical p53 subunits, a tetramer. The region of the protein which allows the formation of this functional p53 tetramer is the so-called tetramerization domain (p53-TD), characterized by its helical structure. Of special importance are the mutations found in this tetramerization domain, since they inhibit the formation of the tetramer and, therefore, its function. Our research focuses on studying how two cancer-related mutations in the p53-TD, L344P and R337H, affect the helicity of the fragment and the formation of its functional tetrameric structure by using nuclear magnetic resonance (NMR). We found that the R337H mutant remained folded in its normal helical structure and was completely in its tetrameric form at a concentration of 100 μM, but was in its monomeric state 11% of the time at a lower concentration of 25 μM. However, the L344P mutant was always found unfolded and in its monomeric state, regardless of the concentration. In this study we show that the mutation L344P severely affects the helicity of the fragment and thus the protein’s ability to tetramerize and suppress tumor formation, while the R337H mutant does not inhibit the formation of the domain’s helical structure, but can still give rise to unfunctional p53 when found at a low concentration.