Prof. Dieter Langosch

Technische Universität München

Project P5: The Conformational Flexibility of Transmembrane Helices in Substrate Recognition and Cleavage


The primary structure of a substrate transmembrane (TM) helix affects its processing by an intramembrane protease. Substrate processing includes multiple levels, such as recognition, translocation, and bond scission. Previous results reveal a complex role of helix flexibility in substrate processing but it remains unclear how exactly the conformational flexibility of a substrate TM helix as well as its mobility in a bilayer are connected to its recognition, uptake, cleavage, and release.



In this project we will systematically assess how site-specific helix flexibility is affected by changing the primary structure of natural and novo designed substrates of γ-secretase, SPPL2 and PARL. Helix flexibility will be related to cleavability performed in other projects of FOR2290. Furthermore, assessing the interactions between TM helices of γ-secretase and various substrates will inform on preferential sites of initial contact.


Publications (FOR 2290)

Different transmembrane domains determine the specificity and efficiency of the cleavage activity of the γ-secretase subunit presenilin.

Schmidt FC, Fitz K, Feilen LP, Okochi M, Steiner H, Langosch D. J Biol Chem. 2023 May;299(5):104626. doi: 10.1016/j.jbc.2023.104626. Epub 2023 Mar 20. PMID: 36944398 Free PMC article.


Cooperation of N- and C-terminal substrate transmembrane domain segments in intramembrane proteolysis by γ-secretase.

Werner NT, Högel P, Güner G, Stelzer W, Wozny M, Aßfalg M, Lichtenthaler SF, Steiner H, Langosch D. Commun Biol. 2023 Feb 15;6(1):177. doi: 10.1038/s42003-023-04470-5. PMID: 36792683 Free PMC article.


Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.

Güner G, Aßfalg M, Zhao K, Dreyer T, Lahiri S, Lo Y, Slivinschi BI, Imhof A, Jocher G, Strohm L, Behrends C, Langosch D, Bronger H, Nimsky C, Bartsch JW, Riddell SR, Steiner H, Lichtenthaler SF. EMBO Mol Med. 2022 Oct 10;14(10):e16084. doi: 10.15252/emmm.202216084. Epub 2022 Sep 7. PMID: 36069059 Free PMC 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


Conformationally Flexible Sites within the Transmembrane Helices of Amyloid Precursor Protein and Notch1 Receptor.

Stelzer W, Langosch D.

Biochemistry. 2019 Jul 2. doi: 10.1021/acs.biochem.9b00505. [Epub ahead of print] PMID: 31264841


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


The Metastable XBP1u Transmembrane Domain Defines Determinants for Intramembrane Proteolysis by Signal Peptide Peptidase.

Yücel SS, Stelzer W, Lorenzoni A, Wozny M, Langosch D, Lemberg MK.

Cell Rep. 2019 Mar 12;26(11):3087-3099.e11. doi: 10.1016/j.celrep.2019.02.057. PMID:30865896


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. 


BLaTM 2.0, a Genetic Tool Revealing Preferred Antiparallel Interaction of Transmembrane Helix 4 of the Dual-Topology Protein EmrE.

Julius A, Laur L, Schanzenbach C, Langosch D.

J Mol Biol. 2017 Jun 2;429(11):1630-1637. doi: 10.1016/j.jmb.2017.04.003. Epub 2017 Apr 19. PMID: 28432015


Substrate processing in intramembrane proteolysis by γ-secretase - the role of protein dynamics.

Langosch D, Steiner H.

Biol Chem. 2017 Apr 1;398(4):441-453. doi: 10.1515/hsz-2016-0269. Review. PMID: 27845877


Identifying ionic interactions within a membrane using BLaTM, a genetic tool to measure homo- and heterotypic transmembrane helix-helix interactions.

Schanzenbach C, Schmidt FC, Breckner P, Teese MG, Langosch D.

Sci Rep. 2017 Mar 7;7:43476. doi: 10.1038/srep43476. PMID: 28266525 Free PMC Article


"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)


"Homodimerization Protects the Amyloid Precursor Protein C99 Fragment from Cleavage by γ-Secretase."

Winkler, E., Julius, A., Steiner, H., Langosch, D. (2015):
Biochemistry. 2015 Oct 13;54(40):6149-52


"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


Publications FOR 2290 PI's

Research Unit FOR 2290