Different Oligomeric States of the Tumor Suppressor p53 Show Identical Binding Behavior towards the S100β Homodimer. (13th April 2022)

• Record Type: Journal Article
• Authors: Wei, Alan An Jung; Iacobucci, Claudio; Schultze, Wiebke; Ihling, Christian H.; Arlt, Christian; Sinz, Andrea
• Is Part Of: Chembiochem. Volume 23:Number 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-13
• Subjects: intrinsically disordered proteins -- mass spectrometry -- p53 -- S100β -- tumor suppressors; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202100665
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: The tumor suppressor protein p53 is a transcription factor that is referred to as the "guardian of the genome" and plays an important role in cancer development. p53 is active as a homotetramer; the S100β homodimer binds to the intrinsically disordered C ‐terminus of p53 affecting its transcriptional activity. The p53/S100β complex is regarded as highly promising therapeutic target in cancer. It has been suggested that S100β exerts its oncogenic effects by altering the p53 oligomeric state. Our aim was to study the structures and oligomerization behavior of different p53/S100β complexes by ESI‐MS, XL‐MS, and SPR. Wild‐type p53 and single amino acid variants, representing different oligomeric states of p53 were individually investigated regarding their binding behavior towards S100β. The stoichiometry of the different p53/S100β complexes were determined by ESI‐MS showing that tetrameric, dimeric, and monomeric p53 variants all bind to an S100β dimer. In addition, XL‐MS revealed the topologies of the p53/S100β complexes to be independent of p53's oligomeric state. With SPR, the thermodynamic parameters were determined for S100β binding to tetrameric, dimeric, or monomeric p53 variants. Our data prove that the S100β homodimer binds to different oligomeric states of p53 with similar binding affinities. This emphasizes the need for alternative explanations to describe the molecular mechanisms underlying p53/S100β interaction. Abstract : By combining ESI‐MS, SPR, and XL‐MS, we investigated the interactions between the tumor suppressor p53 and S100β. Our approach unveiled binding of an S100β dimer to p53, independently from p53's oligomeric state via similar molecular contacts and with comparable binding affinities. The molecular mechanism by which S100β regulates p53 activity goes beyond the currently proposed oligomerization inhibition mechanism.