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.

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.

Membrane lipid remodeling modulates γ-secretase processivity.

Dawkins E, Derks RJE, Schifferer M, Trambauer J, Winkler E, Simons M, Paquet D, Giera M, Kamp F, Steiner H. J Biol Chem. 2023 Apr;299(4):103027. doi: 10.1016/j.jbc.2023.103027. Epub 2023 Feb 16. PMID: 36805335 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.

Active site geometry stabilization of a presenilin homolog by the lipid bilayer promotes intramembrane proteolysis.

Feilen LP, Chen SY, Fukumori A, Feederle R, Zacharias M, Steiner H. Elife. 2022 May 17;11:e76090. doi: 10.7554/eLife.76090. PMID: 35579427 Free PMC article.

Secretases in Alzheimer's disease: Novel insights into proteolysis of APP and TREM2.

Lichtenthaler SF, Tschirner SK, Steiner H. Curr Opin Neurobiol. 2022 Feb;72:101-110. doi: 10.1016/j.conb.2021.09.003. Epub 2021 Oct 22. PMID: 34689040 Review. 

Substrate recruitment by γ-secretase.

Fukumori A, Feilen LP, Steiner H.

Semin Cell Dev Biol. 2020 Sep;105:54-63. doi: 10.1016/j.semcdb.2020.03.006. Epub 2020 Apr 22. PMID: 32331992 Review.

Understanding intramembrane proteolysis by γ-secretase.

Steiner H.

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.

γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.

Steiner A, Schlepckow K, Brunner B, Steiner H, Haass C, Hagn F.

EMBO J. 2020 Aug 24:e104247. doi: 10.15252/embj.2019104247. Online ahead of print. PMID: 32830336

Photo-controlled delivery of very long chain fatty acids to cell membranes and modulation of membrane protein function.

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

Clinical, pathophysiological and genetic features of motor symptoms in autosomal dominant Alzheimer's disease.

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.

Pathogenic Aβ generation in familial Alzheimer's disease: novel mechanistic insights and therapeutic implications.

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

Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation.

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

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.

Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its alpha-Helical Conformation, and Inhibits gamma-Secretase Nonselectively in Liposomes.

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. 

An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function.

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

"Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping."

Fukumori, A. & Steiner, H. (2016):

EMBO J. 2016 May 23. pii: e201694151.

Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74.

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

"Generation and deposition of Aβ43 by the virtually inactive presenilin‐1 L435F mutant contradicts the presenilin loss‐of‐function hypothesis of Alzheimer's disease."

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

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