Structural assessment of the full-length wild-type tumor suppressor protein p53 by mass spectrometry-guided computational modeling.

Autor: Di Ianni A; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany., Tüting C; ZIK HALOmem and Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany., Kipping M; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany., Ihling CH; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany., Köppen J; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany., Iacobucci C; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany.; Department of Physical and Chemical Sciences, University of L'Aquila, Via Vetoio, Coppito, 67100, L'Aquila, Italy., Arlt C; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany. Christian.arlt@pharmazie.uni-halle.de.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany. Christian.arlt@pharmazie.uni-halle.de., Kastritis PL; ZIK HALOmem and Institute of Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany., Sinz A; Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany. andrea.sinz@pharmazie.uni-halle.de.; Center for Structural Mass Spectrometry, Martin Luther University Halle-Wittenberg, Kurt-Mothes-Str. 3, 01620, Halle (Saale), Germany. andrea.sinz@pharmazie.uni-halle.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 May 25; Vol. 13 (1), pp. 8497. Date of Electronic Publication: 2023 May 25.
DOI: 10.1038/s41598-023-35437-5
Abstrakt: The tetrameric tumor suppressor p53 represents a great challenge for 3D-structural analysis due to its high degree of intrinsic disorder (ca. 40%). We aim to shed light on the structural and functional roles of p53's C-terminal region in full-length, wild-type human p53 tetramer and their importance for DNA binding. For this, we employed complementary techniques of structural mass spectrometry (MS) in an integrated approach with computational modeling. Our results show no major conformational differences in p53 between DNA-bound and DNA-free states, but reveal a substantial compaction of p53's C-terminal region. This supports the proposed mechanism of unspecific DNA binding to the C-terminal region of p53 prior to transcription initiation by specific DNA binding to the core domain of p53. The synergies between complementary structural MS techniques and computational modeling as pursued in our integrative approach is envisioned to serve as general strategy for studying intrinsically disordered proteins (IDPs) and intrinsically disordered region (IDRs).
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje