Project P7: Dynamics of Substrate-Protease Interactions
Combining available structural and biochemical data with molecular modeling and simulation methods we will derive structural models in order to advance the understanding of how substrates are recognized and processed by γ-secretase and other intramembrane proteases.
MD simulations and molecular docking will be used to analyze structure, dynamics and enzyme interactions of substrates and to generate putative structural models for substrate binding to γ-secretase. These models will be generated by integrating available experimental data on mutations in the enzyme and substrates and biochemical and biophysical data obtained by experimental FOR2290 groups.
The models will form a basis for understanding the substrate recognition and possible design of inhibitors and modulators.
Spitz C, Schlosser C, Guschtschin-Schmidt N, Stelzer W, Menig S, Götz A, Haug-Kröper M, Scharnagl C, Langosch D, Muhle-Goll C, Fluhrer R.
iScience. 2020 Nov 5;23(12):101775. doi: 10.1016/j.isci.2020.101775. eCollection 2020 Dec 18.PMID: 33294784
The dynamics of γ-secretase and its substrates.
Hitzenberger M, Götz A, Menig S, Brunschweiger B, Zacharias M, Scharnagl C.
Semin Cell Dev Biol. 2020 May 16. pii: S1084-9521(18)30274-X. doi: 10.1016/j.semcdb.2020.04.008. [Epub ahead of print] Review. PMID: 32423851
Modulating Hinge Flexibility in the APP Transmembrane Domain Alters γ-Secretase Cleavage.
Götz A, Mylonas N, Högel P, Silber M, Heinel H, Menig S, Vogel A, Feyrer H, Huster D, Luy B, Langosch D, Scharnagl C, Muhle-Goll C, Kamp F, Steiner H.
Biophys J. 2019 Jun 4;116(11):2103-2120. doi: 10.1016/j.bpj.2019.04.030. Epub 2019 May 3. PMID: 31130234
Götz A, Högel P, Silber M, Chaitoglou I, Luy B, Muhle-Goll C, Scharnagl C, Langosch D.
Sci Rep. 2019 Mar 29;9(1):5321. doi: 10.1038/s41598-019-41766-1. PMID: 30926830
Götz A & Scharnagl C. PLOS ONE 2018.
Glycine Perturbs Local and Global Conformational Flexibility of a Transmembrane Helix.
Högel P, Götz A, Kuhne F, Ebert M, Stelzer W, Rand KD, Scharnagl C, Langosch D.
Stelzer, W., Scharnagl, C., Leurs, U., Rand, K.D., Langosch, D. (2016):
ChemistrySelect, 1: 4403-4407. DOI: 10.1002/slct.201600951 (Supporting Information)
"Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics."
Langosch, D., Scharnagl, C., Steiner, H.,
Lemberg, M.K. (2015)
Trends Biochem Sci. 2015 Jun;40(6):318-27