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
- Mechanism of regulation of proteinkisases CaMKK1, CaMKK2 and ASK1
- Study of inhibition of protease caspase-2 and ligase Nedd4-2 by 14-3-3 protein
- Study of DNA-binding domain of transcription factor FOXO4
EXTERNAL WEBSITE OF THE LABORATORY
Projects
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Phosducin (Pdc), a highly conserved phosphoprotein, plays an important role in the regulation of G-protein signalling, transcriptional control, and modulation of blood pressure. Pdc is negatively regulated by phosphorylation followed by binding to the 14-3-3 protein.
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Our results show the activation of yeast neutral trehalase Nth1 by 14-3-3 proteins from the structural point of view. Our data could be important for understanding of the activation process of Nth1 as well as of the role of 14-3-3 proteins in the regulation of other enzymes.
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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
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
[ASEP]
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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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Pohl; Pavel - Joshi; Rohit - Petrvalská; Olivia - Obšil; Tomáš - Obšilová; Veronika
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14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains
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Communications Biology. 2021; 4(1)); 899
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IF = 6.548
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Obšilová; Veronika - Honzejková; K. - Obšil; Tomáš
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Structural Insights Support Targeting ASK1 Kinase for Therapeutic Interventions
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International Journal of Molecular Sciences. 2021; 22(24)); 13395
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IF = 6.208
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Neves; J. F. - Petrvalská; Olivia - Bosica; F. - Cantrelle; F. X. - Merzougui; H. - O'Mahony; G. - Hanoulle; X. - Obšil; Tomáš - Landrieu; I.
Phosphorylated full-length Tau interacts with 14-3-3 proteins via two short phosphorylated sequences; each occupying a binding groove of 14-3-3 dimer
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FEBS Journal. 2021; 288(6); 1918-1934
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IF = 5.622
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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).
