Dr. Christina Scharnagl

Technische Universität München



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.

 



Publications (FOR 2290)


 

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

 

Increased H-Bond Stability Relates to Altered ε-Cleavage Efficiency and Aβ Levels in the I45T Familial Alzheimer's Disease Mutant of APP.

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

 

Dissecting conformational changes in APP’s transmembrane domain linked to ε-efficiency in familial Alzheimer’s disease.

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.

Biochemistry. 2018 Feb 1. 

 

"The Impact of the ‘Austrian’ Mutation of the Amyloid Precursor Protein Transmembrane Helix is Communicated to the Hinge Region"

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

 


FOR 2290 PI's



Research Unit FOR 2290