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)
iScience. 2020 Nov 5;23(12):101775. doi: 10.1016/j.isci.2020.101775. eCollection 2020 Dec 18.PMID: 33294784
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
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
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.
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
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
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