How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?
Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers...
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MDPI AG
2023-06-01
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| Series: | Current Issues in Molecular Biology |
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| Online Access: | https://www.mdpi.com/1467-3045/45/6/317 |
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| author | Federica Nicolini Toni Todorovski Eduard Puig Mireia Díaz-Lobo Marta Vilaseca Jesús García David Andreu Ernest Giralt |
| author_facet | Federica Nicolini Toni Todorovski Eduard Puig Mireia Díaz-Lobo Marta Vilaseca Jesús García David Andreu Ernest Giralt |
| author_sort | Federica Nicolini |
| collection | DOAJ |
| description | Tumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers, and mutations can alter the oligomeric state of the protein, having an impact on the biological function of the protein and on cell fate decisions. Here, we describe the effects of a number of representative cancer-related mutations on tetramerisation domain (TD) oligomerisation defining a peptide length that permits having a folded and structured domain, thus avoiding the effect of the flanking regions and the net charges at the <i>N</i>- and <i>C</i>-terminus. These peptides have been studied under different experimental conditions. We have applied a variety of techniques, including circular dichroism (CD), native mass spectrometry (MS) and high-field solution NMR. Native MS allows us to detect the native state of complexes maintaining the peptide complexes intact in the gas phase; the secondary and quaternary structures were analysed in solution by NMR, and the oligomeric forms were assigned by diffusion NMR experiments. A significant destabilising effect and a variable monomer population were observed for all the mutants studied. |
| first_indexed | 2024-03-11T02:37:25Z |
| format | Article |
| id | doaj.art-f44ed63b83854cd8b170cb02e58d2cf5 |
| institution | Directory Open Access Journal |
| issn | 1467-3037 1467-3045 |
| language | English |
| last_indexed | 2024-03-11T02:37:25Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj.art-f44ed63b83854cd8b170cb02e58d2cf52023-11-18T09:51:56ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452023-06-014564985500410.3390/cimb45060317How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?Federica Nicolini0Toni Todorovski1Eduard Puig2Mireia Díaz-Lobo3Marta Vilaseca4Jesús García5David Andreu6Ernest Giralt7Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainDepartment of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Dr. Aiguader 88, 08003 Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, SpainTumour suppressor p53 plays a key role in the development of cancer and has therefore been widely studied in recent decades. While it is well known that p53 is biologically active as a tetramer, the tetramerisation mechanism is still not completely understood. p53 is mutated in nearly 50% of cancers, and mutations can alter the oligomeric state of the protein, having an impact on the biological function of the protein and on cell fate decisions. Here, we describe the effects of a number of representative cancer-related mutations on tetramerisation domain (TD) oligomerisation defining a peptide length that permits having a folded and structured domain, thus avoiding the effect of the flanking regions and the net charges at the <i>N</i>- and <i>C</i>-terminus. These peptides have been studied under different experimental conditions. We have applied a variety of techniques, including circular dichroism (CD), native mass spectrometry (MS) and high-field solution NMR. Native MS allows us to detect the native state of complexes maintaining the peptide complexes intact in the gas phase; the secondary and quaternary structures were analysed in solution by NMR, and the oligomeric forms were assigned by diffusion NMR experiments. A significant destabilising effect and a variable monomer population were observed for all the mutants studied.https://www.mdpi.com/1467-3045/45/6/317p53p53 tetramerisation domaincancer mutationsnative MShigh-field NMRdiffusion NMR |
| spellingShingle | Federica Nicolini Toni Todorovski Eduard Puig Mireia Díaz-Lobo Marta Vilaseca Jesús García David Andreu Ernest Giralt How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? Current Issues in Molecular Biology p53 p53 tetramerisation domain cancer mutations native MS high-field NMR diffusion NMR |
| title | How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? |
| title_full | How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? |
| title_fullStr | How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? |
| title_full_unstemmed | How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? |
| title_short | How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain? |
| title_sort | how do cancer related mutations affect the oligomerisation state of the p53 tetramerisation domain |
| topic | p53 p53 tetramerisation domain cancer mutations native MS high-field NMR diffusion NMR |
| url | https://www.mdpi.com/1467-3045/45/6/317 |
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