TY  - JOUR
A1  - Zhang, Qiang
A1  - Balourdas, Dimitrios-Ilias
A1  - Baron, Bruno
A1  - Senitzki, Alon
A1  - Haran, Tali E.
A1  - Wiman, Klas G.
A1  - Soussi, Thierry
A1  - Jörger, Andreas C.
T1  - Evolutionary history of the p53 family DNA-binding domain: insights from an Alvinella pompejana homolog
T2  - Cell death & disease
N2  - The extremophile Alvinella pompejana, an annelid worm living on the edge of hydrothermal vents in the Pacific Ocean, is an excellent model system for studying factors that govern protein stability. Low intrinsic stability is a crucial factor for the susceptibility of the transcription factor p53 to inactivating mutations in human cancer. Understanding its molecular basis may facilitate the design of novel therapeutic strategies targeting mutant p53. By analyzing expressed sequence tag (EST) data, we discovered a p53 family gene in A. pompejana. Protein crystallography and biophysical studies showed that it has a p53/p63-like DNA-binding domain (DBD) that is more thermostable than all vertebrate p53 DBDs tested so far, but not as stable as that of human p63. We also identified features associated with its increased thermostability. In addition, the A. pompejana homolog shares DNA-binding properties with human p53 family DBDs, despite its evolutionary distance, consistent with a potential role in maintaining genome integrity. Through extensive structural and phylogenetic analyses, we could further trace key evolutionary events that shaped the structure, stability, and function of the p53 family DBD over time, leading to a potent but vulnerable tumor suppressor in humans.
KW  - DNA damage response
KW  - Protein folding
KW  - Transcription factors
KW  - Tumour-suppressor proteins
KW  - X-ray crystallography
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/69523
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-695238
SN  - 2041-4889
N1  - Open Access funding enabled and organized by Projekt DEAL.
N1  - We are also grateful for support by the SGC, a registered charity (no: 1097737) that receives funds from AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and US), Merck & Co (aka MSD outside Canada and US), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome [106169/ZZ14/Z].
N1  - Data availability
The coordinates and structure factors of the Alvinella pompejana p53 homolog DBD were deposited in the Protein Data Bank under accession code 7PC6.
VL  - 13
IS  - art. 214
SP  - 1
EP  - 11
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -