Kristin Kaßler

Suche


A2 Computational analysis of linear motifs in effector proteins

Principal investigator
Heinrich Sticht

Mentor
Yves Muller

PhD exam: 14.06.2013

Computational prediction and analysis of interactions between microbial effectors and host proteins

The prevention and treatment of infectious diseases is one of the main topics in modern medicine and pharmacy. Generally, microbes exert pathogenicity by specific interactions of some of their effector proteins with host cell proteins. Therefore, the prediction of novel interactions and the understanding of the underlying molecular mechanisms are pivotal for the development of specific drugs. In this project selected examples of effector-host protein interactions are explored by a computational approach. A comprehensive computer-based investigation includes the analysis of sequence, structure, and dynamics. Sequence-based methods include “blasting” of huge sequence databases for homologous proteins, multiple sequence alignments, and the identification of conserved residues characteristic for a protein family and function. In addition, investigation of the 3D structures of protein complexes can reveal valuable details of the protein interfaces. However, the features, which determine the interactions of biomolecules, cannot fully be understood on the basis of a static protein structure alone as biomolecules are known to display an internal flexibility. In such cases molecular dynamics (MD) is a suitable method to simulate protein motions and to serve as a basis for an energetic analysis of protein-protein interactions on the atomic level.
This study focuses on the Salmonella typhimurium effector SifA, which is essential for the survival and replication of Salmonellae inside the host. In addition, SifA was reported to mediate pathogenicity via the interaction with the cellular protein SKIP and by influencing Rho GTPase activity making the effector a promising target for antibacterial drugs in the treatment of salmonella enteritis.

Figure: Studying the interface of the Salmonella effector SifA with SKIP. A: The bacterium Salmonella. B: Crystal structure of SifA in complex with the cellular protein SKIP. C: Close up view of the respective interface with the sequence motif of SKIP interacting with SifA.

 

Publications

Kassler, K., Meier, J., Eichler, J. and Sticht, H. (2011). Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides. Adv Bioinformatics 2011, 736593.

Meier, J., Kassler, K., Sticht, H,. and Eichler, J. (2011). Exploring Species Selectivity in Protein-Protein Interactions using Synthetic Binding Site Mimetics. Proceedings of the 22nd American Peptide Symposium, American Peptide Society.

Sevvana, M., Kassler, K., Ahnström, J., Weiler, S., Dahlbäck, B., Sticht, H. and Muller, Y. A. (2010). Mouse apoM displays an unprecedented 7-stranded lipocalin fold - Folding decoy or alternative native fold? Mouse apoM displays an unprecedented 7-stranded lipocalin fold - Folding decoy or alternative native fold? J Mol Biol 404, 363-371.

Kassler, K., Horn, A. H. C. and Heinrich Sticht. (2010) Effect of pathogenic mutations on the structure and dynamics of Alzheimer's Aβ42-amyloid oligomers. J Mol Model 16, 1011-1020.

 

Presentations

July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Elucidating the Mechanism of Naturally Occurring HIV-1 gp120 Mutations that Affect CD4-Binding
Talk
     
July 2012 4th Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
The HIV-1 gp120-CD4 Interaction: Investigation from Two Structural Perspectives
Poster
     
March 2012 26th Molecular Modelling Workshop 2012, Erlangen, Germany
One Interface - Two Perspectives Exploration of the HIV-1 gp120 - CD4 Interaction
Poster
     
October 2011 First International SFB 796 Conference: Mechanisms of viral host cell manipulations: from plants to humans, Bamberg, Germany
Structure and Dynamics of the HIV-1 gp120 - CD4 Interaction
Poster
     
July 2011 Summerschool of BIGSS - BioMedTec International Graduate School of Science, University of Bayreuth, Germany
Computational Investigating of Protein Stability, Dynamics and Interactions
Talk and Poster
     
July 2011 3rd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
Investigating Protein Stability, Dynamics and Interaction Using Molecular Dynamics Simulation
Talk and Poster
     
April 2011 Workshop: Computer simulation and Theory of Macromolecules 2011, Hünfeld, Germany
Computational Study of gp120-Binding Properties of Human and Murine CD4
Poster
     
April 2011 25th Molecular Modelling Workshop 2011, Erlangen, Germany
A Murine CD4 Derived Peptide Scaffold to Intervene gp120-CD4 Interaction
Poster
     
March 2011 Keystone Symposium, HIV Pathogenesis, Whistler, Canada
Structural Basis for Species Selectivity in the gp120-CD4 Interaction
Poster
     
September 2010 2nd Annual Retreat, Erlangen School of Molecular Communication, Kloster Banz, Bad Staffelstein, Germany
The Significance of Protein Flexibility: Studying the Importance of gp120 Conformational Sampling for Antibody Recognition
Talk
     
July 2010 Bayreuther Strukturtage 2010, Schloss Thurnau, Germany
Computation Study of HIV-1 gp120 Antibody Recognition and Binding
Talk and Poster
     
March 2010 Keystone Symposium, HIV Vaccines, Banff Canada
Mimetics for HIV-1 Immunization
Poster
     
March 2010 Molecular Modeling Workshop 2010, Erlangen Germany
Computational Study of HIV-1 gp120 Antibody Recognition and Binding
Poster
     
September 2009 First Annual Retreat, Erlangen School of Molecular Communication, Schloss Atzelsberg, Atzelsberg, Germany
Identification and Characterisation of Protein Interfaces: Study of SifA
Talk
     
September 2009 Modeling'09, Annual Molecular Modeling Workshop & Annual International Meeting of the MGMS, Erlangen, Germany
Elucidation of Oligomerization Differences in Pathogenic Alzheimer's Ab42-Amyloid Variants
Poster
     
April 2008 Computer simulation and Theory of Macromolecules, Hünfeld, Germany
Explaining Oligomerization and Fibrillation Tendencies of Ab42-Amyloid Mutants
Poster
     
October 2008 5th Status Symposium Interplay between Molecular Conformations and Biological Functions, Volkswagenstiftung”, Bad Kissingen, Germany
Structural Proposal and Dynamical Behavior of the New Alzheimer Amyloid Ab42 ‘Japanese’ Variant (E22D): Study of the Ab15-42 Pentamer
Poster

 

Awards

Cooperation Award together with Arne Berthelmann and Martin Gießl
3rd Annual Retreat of the Erlangen School of Molecular Communication
Kloster Banz, Bad Staffelstein, Germany, July 2011
"Strukturelle Aufklärung der Bindung zwischen dem potyviralen Hüllprotein PVY-CP und seinem zellulären Interaktionspartner aus N. tabacum." .

Poster Award
24th Molecular Modelling Workshop 2010
Erlangen, Germany, March 2010
"Computational Study of HIV-1 gp120 Antibody Recognition and Binding".