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.

Helical stability of the GnTV transmembrane domain impacts on SPPL3 dependent cleavage.

Papadopoulou AA, Stelzer W, Silber M, Schlosser C, Spitz C, Haug-Kröper M, Straub T, Müller SA, Lichtenthaler SF, Muhle-Goll C, Langosch D, Fluhrer R.

Sci Rep. 2022 Dec 5;12(1):20987. doi: 10.1038/s41598-022-24772-8. PMID: 36470941

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.

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

Physiological functions of SPP/SPPL intramembrane proteases.

Mentrup T, Cabrera-Cabrera F, Fluhrer R, Schröder B.

Cell Mol Life Sci. 2020 Feb 12. doi: 10.1007/s00018-020-03470-6. [Epub ahead of print] Review. PMID: 32052089

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

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1.

Rudan Njavro J, Klotz J, Dislich B, Wanngren J, Shmueli MD, Herber J, Kuhn PH, Kumar R, Koeglsperger T, Conrad M, Wurst W, Feederle R, Vlachos A, Michalakis S, Jedlicka P, Müller SA, Lichtenthaler SF.

FASEB J. 2020 Feb;34(2):2465-2482. doi: 10.1096/fj.201902347R. Epub 2019 Dec 27. PMID: 31908000

Signal Peptide Peptidase-Like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins.

Papadopoulou AA, Müller SA, Mentrup T, Shmueli MD, Niemeyer J, Haug-Kröper M, von Blume J, Mayerhofer A, Feederle R, Schröder B, Lichtenthaler SF, Fluhrer R.

EMBO Rep. 2019 Feb 7. pii: e46451. doi: 10.15252/embr.201846451. [Epub ahead of print] PMID: 30733281

The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban.

Niemeyer J, Mentrup T, Heidasch R, Müller SA, Biswas U, Meyer R, Papadopoulou AA, Dederer V, Haug-Kröper M, Adamski V, Lüllmann-Rauch R, Bergmann M, Mayerhofer A, Saftig P, Wennemuth G, Jessberger R, Fluhrer R, Lichtenthaler SF, Lemberg MK, Schröder B.

EMBO Rep. 2019 Feb 7. pii: e46449. doi: 10.15252/embr.201846449. [Epub ahead of print]

Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C.

Nat Neurosci. 2019 Feb;22(2):191-204. doi: 10.1038/s41593-018-0296-9. Epub 2019 Jan 7. PMID: 30617257

γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding
Manuel Hitzenberger, Martin Zacharias
Front Chem. 2018; 6: 640. Published online 2019 Jan 4. doi: 10.3389/fchem.2018.00640 PMCID: PMC6328467

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

Shedding of BAFF/APRIL Receptors Controls B Cells.

Meinl E, Thaler FS, Lichtenthaler SF.

Trends Immunol. 2018 Sep;39(9):673-676. doi: 10.1016/j.it.2018.07.002. Epub 2018 Jul 30.

Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments.

Lichtenthaler SF, Lemberg MK, Fluhrer R.

EMBO J. 2018 Aug 1;37(15). pii: e99456. doi: 10.15252/embj.201899456. Epub 2018 Jul 5. Review.

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.

Increased γ-Site H-Bond Stability Relates to Altered ϵ-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.

BioRxiv, 372698.

Dissecting conformational changes in APP’s transmembrane domain linked to ε-efficiency in familial Alzheimer’s disease.

Götz A & Scharnagl C.  PLOS ONE 2018.

Click chemistry-mediated biotinylation reveals a function for the protease BACE1 in modulating the neuronal surface glycoproteome

Herber J, Njavro J, Feederle R, Schepers U, Muller U, Brase S, Muller S, Lichtenthaler SF.

Mol Cell Proteomics. 2018.

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. 

CADASIL brain vessels show a HTRA1 loss-of-function Profile.

Zellner A, Scharrer E, Arzberger T, Oka C, Domenga-Denier V, Joutel A, Lichtenthaler SF, Muller SA, Dichgans M, Haffner C.

Acta Neuropathol. 2018.

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. 

Non-cell-autonomous function of DR6 in Schwann cell Proliferation.

Colombo A, Hsia HE, Wang M, Kuhn PH, Brill MS, Canevazzi P, Feederle R, Taveggia C, Misgeld Th, Lichtenthaler SF (2018).

EMBO J. 2018 Apr 3;37(7),

Photoaffinitätsmarkierung: Identifizierung von Substratbindestellen in der γ-Sekretase.

Fukumori, A., Trambauer, J., Feilen, L.P. & Steiner, H. (2018)

BIOspektrum, 2018, 1, 34-36. 

The metalloprotease ADAM10 (a disintegrin and metalloprotease 10) undergoes rapid, postlysis autocatalytic degradation.

Brummer T, Pigoni M, Rossello A, Wang H, Noy PJ, Tomlinson MG, Blobel CP, Lichtenthaler SF.

FASEB J. 2018:fj201700823RR. 

Molecular Pathways for Immune Recognition of Preproinsulin Signal Peptide in Type 1 Diabetes.

Kronenberg-Versteeg D, Eichmann M, Russell MA, de Ru A, Hehn B, Yusuf N, van Veelen PA, Richardson SJ, Morgan NG, Lemberg MK, Peakman M.

Diabetes

Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets?

Mentrup T, Loock AC, Fluhrer R, Schröder B.

Biochim Biophys Acta. 2017 Nov;1864(11 Pt B):2169-2182.

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.

Latest emerging functions of SPP/SPPL intramembrane proteases.

Mentrup T, Fluhrer R, Schröder B.

Eur J Cell Biol. 2017 Aug;96(5):372-382. doi: 10.1016/j.ejcb.2017.03.002. Epub 2017 Mar 16. Review. PMID: 28366434

CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein.

Jules F, Sauvageau E, Dumaresq-Doiron K, Mazzaferri J, Haug-Kröper M, Fluhrer R, Costantino S, Lefrancois S.

Exp Cell Res. 2017 Aug 1;357(1):40-50. doi: 10.1016/j.yexcr.2017.04.024. Epub 2017 Apr 22. PMID: 28442266

The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism.

Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deußing M, Suárez-Calvet M, Mazaheri F, Parhizkar S, Pettkus N, Wurst W, Feederle R, Bartenstein P, Mueggler T, Arzberger T, Knuesel I, Rominger A, Haass C.

EMBO J. 2017 Jul 3;36(13):1837-1853. doi: 10.15252/embj.201796516. Epub 2017 May 30. PMID: 28559417

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

Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue.

Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Müller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K.

Matrix Biol. 2017 May;59:69-79. doi: 10.1016/j.matbio.2016.07.004. Epub 2016 Jul 29. PMID: 27476612

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

An optimised version of the secretome protein enrichment with click sugars (SPECS) method leads to enhanced coverage of the secretome.

Serdaroglu A, Müller SA, Schepers U, Bräse S, Weichert W, Lichtenthaler SF, Kuhn PH.

Proteomics. 2017 Mar;17(5). doi: 10.1002/pmic.201600423. Epub 2017 Jan 31. PMID: 27991726

MT5-MMP Promotes Alzheimer's Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro.

Baranger K, Bonnet AE, Girard SD, Paumier JM, García-González L, Elmanaa W, Bernard A, Charrat E, Stephan D, Bauer C, Moschke K, Lichtenthaler SF, Roman FS, Checler F, Khrestchatisky M, Rivera S.

Front Mol Neurosci. 2017 Jan 10;9:163. doi: 10.3389/fnmol.2016.00163. eCollection 2016. PMID: 28119565 Free PMC Article

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

Proteomic Substrate Identification for Membrane Proteases in the Brain.

Müller SA, Scilabra SD, Lichtenthaler SF.

Front Mol Neurosci. 2016 Oct 13;9:96. eCollection 2016. Review. PMID: 27790089 Free PMC Article

Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.

Pigoni M, Wanngren J, Kuhn PH, Munro KM, Gunnersen JM, Takeshima H, Feederle R, Voytyuk I, De Strooper B, Levasseur MD, Hrupka BJ, Müller SA, Lichtenthaler SF.

Mol Neurodegener. 2016 Oct 5;11(1):67. PMID: 27716410 Free PMC Article

Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function.

Kuhn PH, Colombo AV, Schusser B, Dreymueller D, Wetzel S, Schepers U, Herber J, Ludwig A, Kremmer E, Montag D, Müller U, Schweizer M, Saftig P, Bräse S, Lichtenthaler SF.

Elife. 2016 Jan 23;5. pii: e12748. doi: 10.7554/eLife.12748. PMID: 26802628 Free PMC Article

"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

"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)

"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