Eileen Socher

Suche


A2 Computational analysis of linear interaction motifs and globular protein interfaces in effector proteins

Principal investigator
Heinrich Sticht

Mentor
Yves Muller

Computational studies of short linear motifs in viral proteins

For a long time, it was thought that protein-protein interactions are mediated by large and structured domains. However, the attention shifted from globular domains to disordered regions, for example to the short linear motifs (SLiMs). SLiMs are short sequence motifs in the amino acid sequence. Usually, they are three to ten residues long and encode a functional interaction motif. Although, the SLiMs are non-globular, their binding partners are globular domains.
Furthermore, SLiMs are ubiquitous in eukaryotic proteomes with the result that viruses mimic them to use the cellular mechanisms of the host cell. Viruses, which are obligate intracellular parasites, infect host cells in order to replicate and they need for every step of their life cycle the interaction with cellular proteins. Due to the fact that the interaction between the viral protein and the protein of the host can be mediated through SLiMs, the viruses mimic a host protein short linear motif to hijack and manipulate the cellular protein machinery. For instance the viral proteins mimic motifs of cellular proteins, which are recognized by transport adapters such as importins and exportins. With this trick, viral proteins can get into the nucleus with a nuclear localization sequence (NLS) or exits the nucleus with a nuclear export sequence (NES).
This project will focus on two viral proteins. For these viral proteins we will perform different MD simulations of them in complex with host proteins to gain a better insight into binding and complex stability. First, we will investigate the HTLV p8 protein because in former studies several sequence motifs in the intracellular part of the HTLV p8 protein could be identified and suggest putative interactions with known domains of host proteins. Second, we will study the cytomegaloviral protein pUL97. UL97 contains several autophosphorylation sites within or near the NLS. The presence of phosphorylation sites in the surrounding of NLS is also known for other proteins and the impact (activation or repression of the nuclear import activity) depends on the exact position of the autophosphorylation site within the NLS. Therefore, we want to investigate whether the phosphorylation of the known pUL97 phosphorylation sites causes an activating or inhibitory effect on nuclear import.

Figure: Principle of short linear interaction motifs (SLiMs). Human proteins can interact via short linear motifs (SLiMs). For example, the human protein NFAT interacts with calcineurin over the SPxxxIT calcineurin-binding sequence. The viral protein p12 uses a similar calcineurin-binding motif to mimic the host protein SLiM of NFAT for hijacking and manipulating the cellular protein machinery.

 

Publications

Socher, E., Sticht, H. (2016). Probing the Structure of the Escherichia coli Periplasmic Proteins HdeA and YmgD by Molecular Dynamics Simulations. J Phys Chem B DOI: 10.1021/acs.jpcb.6b06091

Hutterer, C., Hamilton, S., Steingruber, M., Zeitträger, I., Bahsi, H., Thuma, N., Naing, Z., Örfi, Z., Örfi, L., Socher, E., Sticht, H., Rawlinson, W., Chou, S., Haupt, V. J., Marschall, M., (2016). The chemical class of quinazoline compounds provides a core structure for the design and optimization of anticytomegaloviral kinase inhibitors. Antiviral Res 134, 130-143

Steingruber, M., Kraut, A., Socher, E., Sticht, H., Reichel, A., Stamminger, T., Amin, B., Couté, Y., Hutterer, C., Marschall, M. (2016). Proteomic Interaction Patterns between Human Cyclins, the Cyclin-Dependent Kinase Ortholog pUL97 and Additional Cytomegalovirus Proteins. Viruses 8, 219

Oecal, S*., Socher, E*., Uthoff, M., Ernst, C., Zaucke, F., Sticht, H., Baumann, U., Gebauer, J.M*. (2016). The pH-dependent Client Release from the Collagen-Specific Chaperone HSP47 is Triggered by a Tandem Histidine Pair. J Biol Chem 291, 12612-12626 (* these authors contributed equally to this work)

Socher, E., Sticht, H., (2016). Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins. Sci. Rep. 6, 22523; doi: 10.1038/srep22523

Steingruber, M., Socher, E., Hutterer, C., Webel, R., Bergbrede, T., Lenac, T., Sticht, H., Marschall, M. (2015). The Interaction between Cyclin B1 and Cytomegalovirus Protein Kinase pUL97 is Determined by an Active Kinase Domain. Viruses 7, 4582-4601

Socher, E., Sticht, H. and Horn, A.H.C. (2014). The Conformational Stability of Nonfibrillar Amyloid-β Peptide Oligomers Critically Depends on the C-Terminal Peptide Length. ACS Chem Neurosci 5, 161-167

Rogler, A., Hoja, S., Socher, E., Nolte, E., Wach, S., Wieland, S., Hofstädter, F., Goebell, P.J., Wullich, B., Hartmann, A. and Stoehr, R. (2013). Role of two single nucleotide polymorphisms in secreted frizzled related protein 1 and bladder cancer risk. Int J Clin Exp Pathol 6, 1984-1998.

Socher, E., Horn, A.H.C. and Sticht, H. (2013). Is the novel amyloid-β tetramer fold a stable conformation? J Cheminform 5(Suppl 1):P10.

 

Presentations

March 2017 31st Molecular Modelling Workshop, Erlangen, Germany
“Structural investigation of the E. coli proteins HdeA and YmgD by MD Simulations”
Poster
     
March 2017 Workshop on Computer Simulation and Theory of Macromolecules 2017, Hünfeld, Germany
“Structural Investigation of the E. coli Proteins HdeA and YmgD by MD Simulations”
Poster
     
October 2016 8th Annual Retreat, Erlangen School of Molecular Communication, Schloss Schney, Lichtenfels, Germany
”Probing the structure of the Escherichia coli proteins HdeA and YmgD by pH-titrating MD simulations”
Poster
     
September 2016 German Conference on Bioinformatics 2016, Berlin, Germany
”Molecular Dynamics Studies on the pH-Dependent Regulation of Proteins: From Viruses to Plants”
Poster
     
September 2016 Biophysics 2016, Erlangen, Germany
”Probing the structure of the Escherichia coli proteins HdeA and YmgD by pH-titrating MD simulations”
Poster
     
May 2016 Workshop on computer simulation and theory of macromolecules 2016, Hünfeld, Germany
”Investigation of pH-dependent effects on proteins by mimicking pH titration experiments with MD simulations”
Poster
     
April 2016 30th Molecular Modelling Workshop, Erlangen, Germany
”Mimicking titration experiments with MD simulations: A protocol for the investigation of pH-dependent effects on proteins”
Talk
     
April 2016 30th Molecular Modelling Workshop, Erlangen, Germany
”Investigation of pH-dependent effects on proteins by mimicking pH titration experiments with MD simulations”
Poster
     
October 2015 2nd International SFB 796 Conference: Mechanisms of microbial host cell manipulation: From plants to humans, Erlangen, Germany
”Acid Stress Chaperones of E. coli During the Passage through the Host’s Stomach – Observation of a pH-Dependent Dissociation in Molecular Dynamics Simulations”
Poster
     
July 2015 7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany
”pH-Dependent Regulation of Proteins: From Viruses to Plants”
Poster
     
July 2015 Research Day, Emil Fischer Graduate Programme, Erlangen, Germany "pH-Dependent Regulation of Proteins: From Viruses to Plants"
Poster
     
April 2015 Workshop on Computer Simulation and Theory of Macromolecules 2015, Hünfeld, Germany "pH-Dependent Dissociation of HdeA and HdeB Dimers – How E. coli Survives an Acid Trip"
Poster
     
March 2015 29th Molecular Modelling Workshop, Erlangen, Germany "pH-Dependent Dissociation of HdeA and HdeB Dimers"
Poster
     
July 2014 6th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
“pH-dependent dissociation of HdeA dimers-how bacteria survive an acid trip“
Talk
     
May 2014 5th International IZKF-Symposium "Translational Medicine", Kloster Banz, Bad Staffelstein, Germany "The Stability of a Nonfibrillar Amyloid-β Tetramer Structure Depends Critically on C-terminal Peptide Length"
Poster
     
April 2014 Workshop on Computer Simulation and Theory of Macromolecules 2014, Hünfeld, Germany "Computational Investigation of the Hsp47-Collagen Interaction"
Poster
     
March 2014 28th Molecular Modelling Workshop, Erlangen, Germany "H238N Mutant of Hsp47: Molecular Mechanism of Disrupted Collagen Binding"
Poster
     
July 2013 5th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Computational investigation of pH-dependent effects on protein structure and interaction
Talk
     
July 2013 Research Day, Emil Fischer Graduate Programme, Erlangen, Germany
New Amyloid-β Tetramer Structure: Evidence of Conformational Stability
Poster
     
April 2013 Workshop on Computer Simulation and Theory of Macromolecules, 2013, Hünfeld, Germany
New Amyloid-β Tetramer Structure: Evidence of Conformational Stability
Poster
     
February 2013 27th Molecular Modelling Workshop 2013, Erlangen, Germany
Amyloid-β Tetramer: Structural Stability of a New Fold
Poster
     
November 2012 8th German Conference on Chemoinformatics, Goslar, Germany
Is the Novel Amyloid-β Tetramer Fold a Stable Conformation?
Poster
     
August 2012 4th EuCheMS Chemistry Congress, Prague, Czech Republic
Conformational Stability of a Novel Amyloid-β Tetramer Topology
Poster
     
March 2012 26th Molecular Modelling Workshop 2012, Erlangen, Germany
Tetramer of Chimeric Aβ-IgNARs as a Model for Amyloid-β Oligomer Formation in Alzheimer's Disease
Poster
     
June 2011 95. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V., Leipzig, Germany
Role of sFRP1 SNP rs3242 for the risk of prostate and bladder cancer
Poster
     

 

Awards

Best Poster Award

first place

31st Molecular Modelling Workshop 2017, Erlangen, Germany, March 2017
“Structural investigation of the E. coli proteins HdeA and YmgD by MD simulations”

Best Poster Award

first place

Biophysics 2016, Erlangen, Germany
"Probing the structure of the Escherichia coli proteins HdeA and YmgD by pH-titrating MD simulations"

Best Poster Award

first place

7th Annual Retreat, Erlangen School of Molecular Communication, Schloss Hirschberg, Beilngries, Germany, July 2015
“pH-Dependent Regulation of Proteins: From Viruses to Plants“

Best Poster Award

third place

Research Day, Emil Fischer Graduate Programme, Erlangen, Germany, July 2015
“pH-Dependent Regulation of Proteins: From Viruses to Plants“

Best Talk Award

first place

6th Annual Retreat, Erlangen School of Molecular Communication Kloster Banz, Bad Staffelstein, Germany, July 2014
“pH-dependent dissociation of HdeA dimers-how bacteria survive an acid trip“

Best Poster Award

5th International IZKF-Symposium "Translational Medicine",
Kloster Banz, Bad Staffelstein, Germany, May 2014