8P9C

Crystal structure of p63-p73 heterotetramer (tetramerisation domain) in complex with darpin 1810 F11

8P9C の概要

• エントリーDOI: 10.2210/pdb8p9c/pdb
• 分子名称: Tumor protein 63, Tumor protein p73, Darpin 1810 F11, ... (5 entities in total)
• 機能のキーワード: p63, p73, tetramerization domain, darpin, heterotetramer, structural genomics, structural genomics consortium, sgc, dna binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 30536.39

構造登録者

Chaikuad, A.,Strubel, A.,Doetsch, V.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2023-06-05, 公開日: 2023-11-08, 最終更新日: 2023-11-15)

主引用文献

Strubel, A.,Munick, P.,Hartmann, O.,Chaikuad, A.,Dreier, B.,Schaefer, J.V.,Gebel, J.,Osterburg, C.,Tuppi, M.,Schafer, B.,Buck, V.,Rosenfeldt, M.,Knapp, S.,Pluckthun, A.,Diefenbacher, M.E.,Dotsch, V.
DARPins detect the formation of hetero-tetramers of p63 and p73 in epithelial tissues and in squamous cell carcinoma.
Cell Death Dis, 14:674-674, 2023

PubMed Abstract: The two p53 homologues p63 and p73 regulate transcriptional programs in epithelial tissues and several cell types in these tissues express both proteins. All members of the p53 family form tetramers in their active state through a dedicated oligomerization domain that structurally assembles as a dimer of dimers. The oligomerization domain of p63 and p73 share a high sequence identity, but the p53 oligomerization domain is more divergent and it lacks a functionally important C-terminal helix present in the other two family members. Based on these structural differences, p53 does not hetero-oligomerize with p63 or p73. In contrast, p63 and p73 form hetero-oligomers of all possible stoichiometries, with the hetero-tetramer built from a p63 dimer and a p73 dimer being thermodynamically more stable than the two homo-tetramers. This predicts that in cells expressing both proteins a p63/p73 hetero-tetramer is formed. So far, the tools to investigate the biological function of this hetero-tetramer have been missing. Here we report the generation and characterization of Designed Ankyrin Repeat Proteins (DARPins) that bind with high affinity and selectivity to the p63/p73 hetero-tetramer. Using these DARPins we were able to confirm experimentally the existence of this hetero-tetramer in epithelial mouse and human tissues and show that its level increases in squamous cell carcinoma.

PubMed: 37828008
DOI: 10.1038/s41419-023-06213-0

実験手法

X-RAY DIFFRACTION (1.76 Å)