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)


 

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,

 

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.

 

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

 

Research Unit FOR 2290