Our Laboratory is focused on structural biology (the relationship between the structure and function of certain groups of proteins), particularly we focus on the proteins which participate in the signal transmission in the cell. Among methods we use are recombinant protein expression, biophysical characterization, study of intermolecular interactions, protein structure and interaction surfaces. All these methods enable us to better understand the details how the activity and function of protein-protein complexes is regulated. Our research is focused mainly on:
- Structural biology of 14-3-3 proteins and their complexes
- Study of inhibition of ubiquitin ligase Nedd4-2 by 14-3-3 protein
- Characterizaton of the interactions between transcription factor FOXO4 and tumour supressor p53
- Mechanism of regulation of proteinkisases ASK1, CaMKK2 and CaMKK2
EXTERNAL WEBSITE OF THE LABORATORY
Projects
The transcription factor p53 is a key regulator of apoptosis, senescence and DNA repair, which protects cells against tumorigenesis under various cellular stresses. The functions of p53 are closely intertwined with the activity of Forkhead box O (FOXO) transcription factors.
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Our results show the the structural glimpse on the 14-3-3-dependent regulation of human ubiquitin ligase Nedd4-2. Our data could be important for understanding of the regulation process of Nedd4-2 as well as of the role of 14-3-3 proteins in the regulation of other ubiquitin ligases.
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Achievements
Prize of Otto Wichterle for Dr. Dalibor Košek.
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Transcription factor p53 protects cells against tumorigenesis when subjected to various cellular stresses. Under stress conditions, p53 interacts with another transcription factor, FOXO4 (Forkhead box O 4), and together they increase the production of p21 protein, which triggers the process of cell aging (senescence). However, the molecular mechanism of upregulation of p21 transcription is still unclear. In a work published in the Protein Science journal, scientific teams of Dr. Obsilova (IPHYS CAS), prof. Obsil (Faculty of Science, Charles University and IPHYS CAS) and their colleagues from IOCB CAS characterized interactions between p53 and FOXO4 at the molecular level. New knowledge about the structure of the complex may enable the development of specific inhibitors of the interaction between these two proteins, and subsequently in the development of new drugs aimed at the selective elimination of senescent cells.
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Two accepted papers in Communications Biology: July and August 2021
Pavel Pohl, Rohit Joshi, Olivia Petrvalska, Tomas Obsil and Veronika Obsilova
14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains | Communications Biology (nature.com)
Commun. Biol. 2021 July 22; 4(1):899.
Matej Horvath, Olivia Petrvalska, Petr Herman, Tomas Obsil and Veronika Obsilova
14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites | Communications Biology (nature.com)
Commun. Biol. 2021 August 19; 4(1):986.
IF = 6.268
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The study published in prestigious journal eLife identifies small molecule compounds that interact with the Forkhead box O3 transcription factor (FOXO3) and modulate its activity.
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Publications
Sechovcová; Hana - Rudl Kulhavá; Lucie - Fliegerová; Kateřina - Killer; Jiří - Kopečný; Jan
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Advantages of label free method in comparison with 2DE proteomic analysis of Butyrivibrio fibrisolvens 3071 grown on different carbon sources
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Italian Journal of Animal Science. 2022; 21(1); 1508-1519
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IF = 2.552
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Obšilová; Veronika - Obšil; T.
Structural insights into the functional roles of 14-3-3 proteins
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Frontiers in molecular biosciences. 2022; 9(Sep 16)); 1016071
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IF = 6.113
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Mandal; R. - Kohoutová; Klára - Petrvalská; Olivia - Horváth; M. - Srb; Pavel - Veverka; Václav - Obšilová; Veronika - Obšil; Tomáš
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FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA
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Protein Science. 2022; 31(5)); e4287
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IF = 6.993
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Kohoutová; Klára - Dočekal; V. - Ausserlechner; M. J. - Kaiser; N. - Tekel; A. - Mandal; R. - Horváth; M. - Obšilová; Veronika - Veselý; J. - Hagenbuchner; J. - Obšil; Tomáš
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Lengthening the Guanidine–Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription
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ACS Omega. 2022; 7(38); 34632-34646
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IF = 4.132
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Joshi; Rohit - Pohl; Pavel - Strachotová; D. - Herman; P. - Obšil; Tomáš - Obšilová; Veronika
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Nedd4-2 binding to 14-3-3 modulates the accessibility of its catalytic site and WW domains
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Biophysical Journal. 2022; 121(7); 1299-1311
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IF = 3.699
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Detailed insight on structure of the complex 14-3-3:Nth1 (PDB 5M4A). Alblova et al. (2017).
A) Identification of key phosphorylation sites responsible for 14-3-3-dependent activation of neutral trehalase Nth1. B) Decrease of H/D kinetics for a peptide in Ca-binding domain which lies on the interface between the two proteins induced by Bmh1. C) SAXS low resolution structure of the Nth1:Bmh1 complex. Veisova et al. (2012), Macakova et al. (2013), Kopecka et al. (2014).
Protein 14-3-3 interacts with N- and C-termini of Gtβγ binding interfaces of phosducinu. Kacirova et al. (2015).
