Project P4: Substrate Recognition and Cleavage by γ-Secretase
γ-Secretase is a pivotal intramembrane protease and major Alzheimer disease (AD) drug target. Besides the AD-associated β-amyloid precursor protein (APP) substrate C99, the enzyme has about hundred other substrates. Despite successful structure determination of γ-secretase, it is still only poorly understood how its substrates are recognized and selected.
We could already identify the binding sites of C99 at the amino acid level as well as the subunits to which C99 substrate binds. In continuation we will now also determine the precise contact points of C99 at the amino acid level of the protease. Finally, we want to identify sequence determinants of γ-secretase substrates, which are important for recognition and cleavage and which allow distinguishing them from non-substrates. We expect that our continuous studies, in close collaboration with other groups of the FOR2990 network, will reveal fundamental knowledge on how intramembrane proteases recruit and cleave their substrates.
Publications (FOR 2290)
Understanding intramembrane proteolysis by γ-secretase.
Semin Cell Dev Biol. 2020 Sep;105:1-2. doi: 10.1016/j.semcdb.2020.06.004. Epub 2020 Jun 18. PMID: 32565391 No abstract available.
EMBO J. 2020 Aug 24:e104247. doi: 10.15252/embj.2019104247. Online ahead of print. PMID: 32830336
Kong L, Dawkins E, Campbell F, Winkler E, Derks RJE, Giera M, Kamp F, Steiner H, Kros A.
Biochim Biophys Acta Biomembr. 2020 May 1;1862(5):183200. doi: 10.1016/j.bbamem.2020.183200. Epub 2020 Jan 20. PMID: 31972163
Vöglein J, Paumier K, Jucker M, Preische O, McDade E, Hassenstab J, Benzinger TL, Noble JM, Berman SB, Graff-Radford NR, Ghetti B, Farlow MR, Chhatwal J, Salloway S, Xiong C, Karch CM, Cairns N, Mori H, Schofield PR, Masters CL, Goate A, Buckles V, Fox N, Rossor M, Chrem P, Allegri R, Ringman JM, Höglinger G, Steiner H, Dieterich M, Haass C, Laske C, Morris JC, Bateman RJ, Danek A, Levin J; Dominantly Inherited Alzheimer Network. Brain. 2019 May 1;142(5):1429-1440. doi: 10.1093/brain/awz050.
Trambauer J, Fukumori A, Steiner H.
Curr Opin Neurobiol. 2020 Feb 24;61:73-81. doi: 10.1016/j.conb.2020.01.011. [Epub ahead of print] Review. PMID: 32105841
Trambauer J, Rodríguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H.
EMBO Rep. 2020 Jan 7;21(1):e47996. doi: 10.15252/embr.201947996. Epub 2019 Nov 25.
PMID: 31762188
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
Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis.
Mentrup T, Theodorou K, Cabrera-Cabrera F, Helbig AO, Happ K, Gijbels M, Gradtke AC, Rabe B, Fukumori A, Steiner H, Tholey A, Fluhrer R, Donners M, Schröder B.
J Exp Med. 2019 Apr 1;216(4):807-830. doi: 10.1084/jem.20171438. Epub 2019 Feb 28. PMID: 30819724
Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase
Harald Steiner, Akio Fukumori, Shinji Tagami and Masayasu Okochi (2018).
Cell Stress 2(11): 292-310. doi: 10.15698/cst2018.11.162
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,
Kamp F, Scheidt HA, Winkler E, Basset G, Heinel H, Hutchison JM, LaPointe LM, Sanders CR, Steiner H, Huster D.
ACS Chem Neurosci. 2018.
Photoaffinitätsmarkierung: Identifizierung von Substratbindestellen in der γ-Sekretase.
Fukumori, A., Trambauer, J., Feilen, L.P. & Steiner, H. (2018)
BIOspektrum, 2018, 1, 34-36.
Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C.
EMBO Mol Med. 2017 Oct;9(10):1356-1365.
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
Analyzing Amyloid-β Peptide Modulation Profiles and Binding Sites of γ-Secretase Modulators.
Trambauer J, Fukumori A, Kretner B, Steiner H.
Methods Enzymol. 2017;584:157-183. doi: 10.1016/bs.mie.2016.10.013. Epub 2016 Dec 1. PMID: 28065262
Fukumori, A. & Steiner, H. (2016):
EMBO J. 2016 May 23. pii: e201694151.
Hüttl S, Helfrich F, Mentrup T, Held S, Fukumori A, Steiner H, Saftig P, Fluhrer R, Schröder B.
Biochem J. 2016 May 15;473(10):1405-22. doi: 10.1042/BCJ20160156. Epub 2016 Mar 17. PMID: 26987812
Kretner, B., Trambauer, J., Fukumori, A., Mielke, J., Kuhn, P-H., Kremmer, E., Giese, A. , Lichtenthaler, S.F., Haass, C., Arzberger, T., Steiner, H. (2016):
EMBO Molecular Medicine. 2016. e201505952.
Proteolytic Processing of Neuregulin 1 Type III by Three Intramembrane-cleaving Proteases.
Fleck D, Voss M, Brankatschk B, Giudici C, Hampel H, Schwenk B, Edbauer D, Fukumori A, Steiner H, Kremmer E, Haug-Kröper M, Rossner MJ, Fluhrer R, Willem M, Haass C.
J Biol Chem. 2016 Jan 1;291(1):318-33. doi: 10.1074/jbc.M115.697995. Epub 2015 Nov 16. PMID: 26574544 Free PMC Article
"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