Project P8: Investigation of Molecular Dynamics of Substrate Transmembrane α-Helices by Solution and Solid-State NMR Spectroscopy
In this project, we investigate the structure and dynamics of transmembrane (TM) proteases’ substrates using a combination of solution and solid-state NMR spectroscopy. As the exact mechanism by which transmembrane proteases recognize their substrates is still not clear, we investigate if the molecular dynamics of a TM helix may determine its suitability as a substrate for intramembrane proteolysis.
To this end, we will apply numerous NMR techniques in solution and in membrane reconstituted systems. In close collaborations with the cell biology and computer simulation groups within the consortium this approach will shed more light on the mechanism by which transmembrane proteases recognize/bind and process their substrates.
Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state.
Siebert V, Silber M, Heuten E, Muhle-Goll C, Lemberg MK.
J Biol Chem. 2022 Jul 31:102321. doi: 10.1016/j.jbc.2022.102321. Online ahead of print.PMID: 35921890 Free article.
Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.
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
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
Stabilization / destabilization of the APP transmembrane domain by mutations in the di-glycine hinge alter helical structure and dynamics, and impair cleavage by γ-secretase
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. BioRxiv, 375006. https://doi.org/10.1101/375006