Language：English   Publisher：Chembiochem  

Li–Fraumeni syndrome (LFS) is an inherited cancer predisposition disorder caused by heterozygous TP53 mutations. Among these, missense mutations at Arg337—such as R337C and R337H—are common in LFS patients. Although many studies have characterized individual p53 variants in LFS, the impact of tetramerization domain (TD) mutations on wild-type (WT) p53 function remains unclear. Herein, a novel FRET-based assay system that enables the simultaneous detection of heterotetramer formation and p53-dependent transcriptional activity in live cells is developed. These results show that the heteromultimerization of the R337C variant with WT p53 is only slightly reduced compared to WT homotetramers, yet its transcriptional activity is diminished by over 50%. In contrast, the R337H variant forms heterotetramers at near-normal levels but exhibits markedly compromised transcriptional activity. These findings reveal a previously unrecognized dominant-negative-like effect, suggesting reduced p53 function is due not only to decreased tetramer formation but also to diminished heterotetramer stability. Moreover, the LFS-associated p53TD variants show a greater loss of activity against the low-affinity, apoptosis-inducing bax response element than against the high-affinity, cell cycle arrest-related CDKN1A response element. Collectively, this study demonstrates that p53TD mutations can exert dominant-negative effects, advancing the understanding of p53 heteromultimer function in LFS pathogenesis. These mechanistic insights into p53 heterotetramer stability may not only inform genetic screening strategies for LFS but also support future therapeutic approaches aimed at restoring p53 function by stabilizing mutant tetramers.

DOI： 10.1002/cbic.202500330

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Language：English   Publisher：Biomimetics  

Biomineralization peptides are versatile tools for generating nanostructures since they can make specific interactions with various inorganic metals, which can lead to the formation of intricate nanostructures. Previously, we examined the influence that multivalency has on inorganic structures formed by p53 tetramer-based biomineralization peptides and noted a connection between the geometry of the peptide and its ability to regulate nanostructure formation. To investigate the role of multivalency in nanostructure formation by biomineralization peptides more thoroughly, silver biomineralization peptides were engineered by linking them to additional self-assembling molecules based on coiled-coil peptides and multistranded DNA oligomers. Under mild reducing conditions at room temperature, these engineered biomineralization peptides self-assembled and formed silver nanostructures. The trimeric forms of the biomineralization peptides were the most efficient in forming a hexagonal disk nanostructure, with both the coiled-coil peptide and DNA-based multimeric forms. Together, the results suggest that the spatial arrangement of biomineralization peptides plays a more important role in regulating nanostructure formation than their valency.

DOI： 10.3390/biomimetics8080606

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Language：English   Publisher：International Journal of Molecular Sciences  

The p53 protein is a transcriptional regulatory factor and many of its functions require that it forms a tetrameric structure. Although the tetramerization domain of mammalian p53 proteins (p53TD) share significant sequence similarities, it was recently shown that the tree shrew p53TD is considerably more thermostable than the human p53TD. To determine whether other mammalian species display differences in this domain, we used biophysical, functional, and structural studies to compare the properties of the p53TDs from six mammalian model organisms (human, tree shrew, guinea pig, Chinese hamster, sheep, and opossum). The results indicate that the p53TD from the opossum and tree shrew are significantly more stable than the human p53TD, and there is a correlation between the thermostability of the p53TDs and their ability to activate transcription. Structural analysis of the tree shrew and opossum p53TDs indicated that amino acid substitutions within two distinct regions of their p53TDs can dramatically alter hydrophobic packing of the tetramer, and in particular substitutions at positions corresponding to F341 and Q354 of the human p53TD. Together, the results suggest that subtle changes in the sequence of the p53TD can dramatically alter the stability, and potentially lead to important changes in the functional activity, of the p53 protein.

DOI： 10.3390/ijms242316620

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Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：(公社)日本薬学会  

Authorship：Lead author  

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