SFB796 - Sub project A2

Suche


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

 

Project summary

The project focuses on the prediction and structural characterization of host-pathogen protein interactions using computational tools. Such recognition processes either occur between short sequence motifs that bind complementary adapter modules or between pairs of globular protein domains. These types of interactions do not only differ from a structural point of view but also with respect to the computational tools required for their prediction and analysis.
One particular problem for the prediction of functional interaction motifs is the short length of the respective sequence patterns resulting in a large number of false-positive hits, which prove to be non-functional in subsequent experiments. Therefore, we aim to improve the specificity of the predictions by assessing the importance of motif-specific flanking sequence regions. Method development will be performed using the SUMO-interaction motifs as a model system, for which a large dataset of binding and non-binding instances is available. In order to further increase the reliability of the predictions, modeling of sequence motifs in complex with the respective adapter domains will be performed, what will allow judging the likelihood of an interaction based on a three-dimensional structure. In collaboration with experimental groups from this CRC, this approach will be applied to various microbial effectors including the cytomegaloviral proteins pUS27, pUS28, pUL50, pUL97, and ligands of plant-type Hsp40-chaperones
For the host-pathogen interactions formed between globular proteins domains, a combination of molecular modeling, docking, and molecular dynamics simulations will be used. The latter technique provides information about the conformational stability and energetics of an interaction that can hardly be deduced from static structures alone. These methods will be applied to study the structure of the cytomegaloviral regulator protein IE1 and the interaction with its cellular targets PML and p107. Moreover, we will also investigate the ability of the viral G-protein coupled receptors pUS27 and pUS28 to form heterodimers with cellular GPCRs. Both projects are collaborations with experimental groups from the CRC, which will allow a subsequent verification of the computational predictions.




Complex structure of the bacterial effector protein SifA (grey surface) with a cellular target protein. Residues important for specific recognition are shown in stick presentation.

 

Project relevant publications

  • Rücker, P., Wieninger, S.A., Ullmann, G.M., Sticht, H.   (2012).   pH-Dependent molecular dynamics of vesicular stomatitis virus glycoprotein G.   Proteins   [in press].

  • Webel, R., Solbak, S.M., Held, C., Milbradt, J., Groß, A., Eichler, J., Wittenberg, T., Jardin, C., Sticht, H., Fossen, T. & Marschall, M.   (2012).   Nuclear import of isoforms of the cytomegalovirus kinase pUL97 is mediated by differential activity of NLS1 and NLS2 both acting through classical importin-α binding.   J. Gen. Virol. 93, 1756-68.

  • Milbradt, J., Auerochs, S., Sevvana, M., Muller, Y.A., Sticht, H. & Marschall, M.   (2012).   Specific Residues of a Conserved Domain in the N Terminus of the Human Cytomegalovirus pUL50 Protein Determine Its Intranuclear Interaction with pUL53.   J. Biol. Chem. 287, 24004-16.

  • Mazumder, E.D., Jardin, C., Vogel, B., Heck, E., Scholz, B., Lengenfelder, D., Sticht, H. & Ensser, A.   (2012).   A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein Tip.   PLoS ONE 7, e34306.

  • Jardin, C. & Sticht, H.   (2012).   Identification of the structural features that mediate binding specificity in the recognition of STAT proteins by Dual-Specificity Phosphatases.   J. Biomol. Struct. Dyn. 29, 777-792.

  • Kassler, K., Meier, J., Eichler, J. & 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, 736593.

  • Meier, J., Kassler, K., Sticht, H. & Eichler, J.   (2011).   Exploring Species Selectivity in Protein-Protein Interactions using Synthetic Binding Site Mimetics.   pp. 206-207, Peptides: Proceedings of the 22nd American Peptide Symposium, Imperial Prompt Scientific Publishing, San Diego, USA (ISBN 978-0-9839741-0-9).

  • Pötzsch, S., Spindler, N., Wiegers, A.-K., Fisch, T., Rücker, P., Sticht, H., Grieb, N., Baroti, T., Weisel, F., Stamminger, T., Martin-Parras, L., Mach, M. and Winkler, T.H.   (2011).   B cell repertoire analysis identifies new antigenic domains on glycoprotein B of human cytomegalovirus which are target of neutralizing antibodies.   PLoS Pathogens 7(8), e1002172.

  • Rücker, P., Horn, A.H.C., Meiselbach, H. & Sticht, H.   (2011).   A comparative study of HIV-1 and HTLV-I protease structure and dynamics reveals a conserved residue interaction network.   J. Mol. Model. 17, 2693-2705.

  • Seebahn, A., Dinkel, H., Mohrlüder, J., Hartmann, R, Vogel, N., Becker, C.-M., Sticht, H. & Enz, R.   (2011).   Structural characterization of intracellular C-terminal domains of group III metabotropic glutamate receptors.   FEBS Lett. 585, 511-516.

  • Dütting, E., Schröder-Kreß, N., Sticht, H. & Enz, R.   (2011).   Sumo E3 ligases are expressed in the retina and regulate sumoylation of the metabotropic glutamate receptor 8b.   Biochem. J. 435, 365-371.

  • Webel, R., Milbradt, J., Auerochs, S., Schregel, V., Held, C., Nöbauer, K., Razzazi-Fazeli, E., Jardin, C., Wittenberg, T., Sticht, H. & Marschall, M.   (2011).   Two isoforms of the protein kinase pUL97 of human cytomegalovirus are differentially regulated in their nuclear translocation.   J. Gen. Virol. 92, 638-649.

  • Meiselbach, H. & Sticht, H.   (2011).   Effect of the SH3-SH2 Domain Linker Sequence on the Structure of Hck Kinase.   J. Mol. Model. 17, 1927-1934.

  • Dirauf, P., Meiselbach, H. & Sticht, H.   (2010).   Effects of the V82A and I54V mutations on the dynamics and ligand binding properties of HIV-1 protease.   J. Mol. Model. 16, 1577-1583.

  • Milbradt, J., Webel, R., Auerochs, S., Sticht, H. & Marschall, M.   (2010).   Novel mode of phosphorylation-triggered reorganization of the nuclear lamina during nuclear egress of human cytomegalovirus.   J. Biol. Chem. 285, 13979-13989.

  • Milbradt, J., Auerochs, S., Sticht, H. & Marschall, M.   (2009).   Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex.   J. Gen. Virol. 90, 579-590.

  • Dinkel, H. and Sticht, H.   (2007).   A computational strategy for the prediction of functional linear peptide motifs in proteins.   Bioinformatics 23, 3297-3303.