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Fluhrer Lab

Research Projects

 

The research group of Prof. Dr. Regina Fluhrer focuses on proteolytic processes in cellular membranes. The key figures in these processes are intramembrane proteases. They play an important role in reverse signal transduction and degradation of membrane proteins. One class of these proteases is represented by the GxGD aspartyl proteases. GxGD describes a conserved amino acid motif in the active center that distinguishes these proteases from conventional aspartyl proteases.

 

The family of signal peptide peptidase (SPP) and its homologues (SPPL) belongs to the class of GxGD aspartyl proteases. In humans, five representatives of the SPP / SPPL protease family are known SPP, SPPL2a, SPPL2b, SPPL2c and SPPL3.

SPP/SPPL family created by Kinda Sharrouf with BioRender.com

SPP/SPPL Proteases in Disease Context

SPP/SPPL proteases are increasingly discussed as therapeutic targets for treatment of neurodegenerative, immunological and oncological diseases as well as of viral infections and malaria. Cellular glycan structures also appear to play an important role in the development of these diseases, but mechanisms of this phenomenon are not yet understood in detail.

 

Our research indicates that SPPL3 is the main protease for the release of the luminal domain of various glycosyltransferases and glycosidases. Since the catalytic center of glycan-modifying enzymes is located in their ectodomain, release of these enzymes reduces their catalytic activity in the Golgi Aparatus. Consequently, the amount of expressed SPPL3 influences the glycosylation status of secreted and membrane proteins. Thus, increased SPPL3 expression results in hypoglycosylationof many secretory and membrane proteins, while reduced levels of SPPL3 induce hyperglycosylated proteins.

 

In addition, various representatives of the SPP/SPPL protease family have a pronounced expression in different types of immune cells and are involved in the differentiation of these cells.

 

We therefore aim to understand how activity and expression of SPP/SPPL proteases are changed in the context of diseases, with a focus on understanding SPPL3-related changes in glycan patterns in context of tumor development and metastasis.

Potentielle Rolle von GxGD-Aspartylproteasen im Rahmen der Tumorentstehung Charlotte Spitz

Regulation and Physiological Function of SPP/SPPL proteases

SPP/SPPL proteases cleave a number of different substrates, including a variety of glycan-modifying enzymes. Thus, changing expression or activity of these proteases can quickly change molecular processes in the cell.

 

For instance, altered SPPL3 expression changes the glycan pattern of many secretory and membrane proteins and, thus, also that of the extracellular matrix. But cleavage of immunologically relevant proteins such as TNFαor CD74 can also quickly change function and metabolism of cells.

 

Despite this function as a molecular switch and intensive research, to date neither the regulation nor the physiological function of the SPP/SPPL proteases is fully understood. Our ongoing research projects therefore aim to identify additional substrates for these enzymes and to elucidate the molecular mechanisms of their regulation. In particular, we are investigating how food components and other environmental factors influence these proteases.

Impact of SPPL3 on protein glycosylation Matthias Voss
Voss Matthias, Künzel Ulrike, Higel Fabian, Kuhn Peer‐Hendrik, Colombo Alessio, Fukumori Akio, Haug‐Kröper Martina, Klier Bärbel, Grammer Gudula, Seidl Andreas, Schröder Bernd, Obst Reinhard, Steiner Harald, Lichtenthaler Stefan F., Haass Christian, Fluhrer Regina. Shedding of glycan‐modifying enzymes by signal peptide peptidase‐like 3 (SPPL3) regulates cellular N‐glycosylation. EMBO Journal 2014;33(24):2890-2905. https://doi.org/10.15252/embj.201488375
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Substrate Recognition and Processing by SPP/SPPL proteases

In contrast to soluble proteases, intramembrane proteases recognize and cleave their substrates within the hydrophobic core of the membrane. However, the mechanisms of substrate recognition and processing as well as the molecular requirements that qualify a substrate as such are still not fully understood. The best-studied intramembraneproteasein this regard is γ-secretase. Extensive studies over the past 25 years suggest a multistep cleavage model for substrate processing and for recognition the dynamics of substrates transmembrane domain seems to play an important role. Studies on the SPPL2b protease indicate that this protease uses a very similar cleavage model.

 

Whether other members of the SPP/SPPL family use comparable mechanisms for substrate processing and how substrates can be predicted with the help of artificial intelligence (AI) is subject of ongoing and future research projects.

Substratprozessierung druch SPPL2b (© Charlotte Spitz)

Partners

The research group of Prof. Dr. Regina Fluhrer collaborates with many leading national and international institutions.

 

In a longstanding cooperation with Prof. Dr. Bernd Schröder from the Institute of Physiological Chemistry at the Technical University of Dresden, the research group of Prof. Fluhreris investigating the physiological function of SPP/SPPL proteases. The collaboration particularly enables the efficient use of various model systems.

In a joint study, we were able to show that SPPL2c, a so far uncharacterized representative of the GxGDaspartyl proteases, impacts on the vesicular transport in cells and is involved in the efficient maturation of male germ cells.

 

 

Publications

Papadopoulou Alkmini A, Müller Stephan A, Mentrup Torben, Shmueli Merav D, Niemeyer Johannes, Haug-Kröper Martina, von Blume Julia, Mayerhofer Artur, Feederle Regina, Schröder Bernd, Lichtenthaler Stefan F, Fluhrer Regina. Signal peptide peptidaselike 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins. EMBO reports 2019;20(3):e46451.

Link to publication

 

Niemeyer Johannes, Mentrup Torben, Heidasch Ronny, Müller Stehphan A, Biswas Uddipta, Meyer Rieke, Papadoupoulou Alkmini A, Dederer Verena, Haug-Kröper Martina, Adamski Vivian, Lüllmann-Rauch Renate, Bergmann Martin, Mayerhofer Artur, Saftig Paul, Wennemuth Gunther, Jessberger Rolf, Fluhrer Regina, Lichtenthaler Stefan F, Lemberg Marius K, Schröder Bernd. The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. EMBO reports 2019;20(3):e46449.

Link to publication

Together with the Chair for Neuroproteomicsat the German Center for Neurodegenerative Diseases, DZNE and at the Technical University of Munich, the research group of Prof. Fluhrer aims to identify new substrates for intramembrane proteases and to determine the cleavage sites within these substrates.

With help of modern mass spectrometry, we significantly expanded the range of known substrates for both the SPPL3 and the SPPL2c protease.

 

 

Publications

Papadopoulou Alkmini A, Müller Stephan A, Mentrup Torben, Shmueli Merav D, Niemeyer Johannes, Haug-Kröper Martina, von Blume Julia, Mayerhofer Artur, Feederle Regina, Schröder Bernd, Lichtenthaler Stefan F, Fluhrer Regina. Signal peptide peptidase-like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins. EMBO reports 2019;20(3):e46451.

Link to publication

 

Kuhn Peer-Hendrik, Voss Matthias, Haug-Kröper Martina, Schröder Bernd, Schepers Ute, Bräse Stefan, Haass Christian, Lichtenthaler Stefan F., Fluhrer Regina. Secretome analysis identifies novel signal peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways. Molecular & Cellular Proteomics 2015;14(6):1584-1598.

Link to publication

In collaboration with Prof. Dr. Nathan Singh at the Washington University School of Medicine, Saint Louis, we were able to show that malignant B cells with lower SPPL3 expression have an increased resistance to treatment with chimeric antigen receptor (CAR) T cells against CD19. CAR T cell therapy against CD19 is used to treat acute lymphoblastic leukemia (ALL). However, the development of resistance is a major problem. Variations in SPPL3 expression can explain the phenomenon and, thus, are the basis for further developing this therapy in the future.

 

 

Publication

Amanda Heard, Jack H Landmann, Ava R Hansen, Alkmini Papadopolou, Yu-Sung Hsu, Mehmet Emrah Selli, John M Warrington, John Lattin, Jufang Chang, Helen Ha, Martina Haug-Kroeper, Balraj Doray, Saar Gill, Marco Ruella, Katharina E Hayer, Matthew D Weitzman, Abby M Green, Regina Fluhrer, Nathan Singh. Antigen glycosylation regulates efficacy of CAR T cells targeting CD19 Nat Commun. 2022 Jun 11;13(1):3367.

Link to publication

Funding

Intramural Research Funding

„Forschungspotenziale besser nutzen!“, University of Augsburg – Funding since 2024

 

Third Party Funding

DFG Research Grant: Biological function and molecular mechanisms of intramembrane proteoylsisby Signal Peptide Peptidase Like-3 (SPPL3) - Funding since 2014

 

Project within the DFG Research Group FOR 2290: Substrate recognition and binding by Signal Peptide Peptidase-like 2 (SPPL2) family - Funding since 2015-2023

 

DFG Research Grant: Mechanisms and Function of Intramembrane Proteolysis by the γ-secretase homologous Signal Peptide Peptidase-like Proteases (SPPL) - Funding 2006 - 2014

 

Forschungsgroßgeräte

Cell metabolism-analyzer - Funding in 2022

Publications

2024 | 2023 | 2022 | 2020 | 2019 | 2018 | 2017 | 2016 | 2015 | 2014 | 2013 | 2012 | 2011 | 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2003 | 2002 | 2001

2024
Sharrouf Kinda, Schlosser Christine, Mildenberger Sandra, Fluhrer Regina, Hoeppner Sabine. In vitro cleavage of tumor necrosis factor α (TNFα) by Signal-Peptide-Peptidase-like 2b (SPPL2b) resembles mechanistic principles observed in the cellular context. Chemico-Biological Interactions 2024;111006. https://doi.org/10.1016/j.cbi.2024.111006
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Maccioni Riccardo, Travisan Caterina, Badman Jack, Zerial Stefania, Wagener Annika, Andrade-Talavera Yuniesky, Picciau Federico, Grassi Caterina, Chen Gefei, Lemoine Laetitia, Fisahn André, Jiang Richeng, Fluhrer Regina, Mentrup Torben, Schröder Bernd, Nilsson Per, Tambaro Simone. Signal peptide peptidase-like 2b modulates the amyloidogenic pathway and exhibits an Aβ-dependent expression in Alzheimer's disease. Progress in Neurobiology 2024;102585. https://doi.org/10.1016/j.pneurobio.2024.102585
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Mentrup Torben, Leinung Nadja, Patel Mehul, Fluhrer Regina, Schröder Bernd. The role of SPP/SPPL intramembrane proteases in membrane protein homeostasis. The FEBS Journal 2024;291(1):25-44. https://doi.org/10.1111/febs.16941
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2023
Smit P., Buehring-Uhle C., Nather C., Negraschus A., Goldmann U., Papadopoulou Alkmini A., Riviere J., Morath V., Henkel E., Bromberger T., Goetze K., Heinz L., Fluhrer Regina, Moser M., Superti-Furga G., Bassermann F., Eichner R.. Inhibiting MGAT1-mediated N-glycosylation reduces proliferation and adhesion of AML cells and increases affinities of anti-SLC3A2 directed immunotherapies [Abstract]. Oncology Research and Treatment 2023;46(Suppl. 5):191. https://doi.org/10.1159/000533576
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Hoeppner Sabine, Schröder Bernd, Fluhrer Regina. Structure and function of SPP/SPPL proteases: insights from biochemical evidence and predictive modeling. The FEBS Journal 2023;290(23):5456-5474. https://doi.org/10.1111/febs.16968
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2022
Heard Amanda, Landmann Jack H., Hansen Ava R., Papadopolou Alkmini, Hsu Yu-Sung, Selli Mehmet Emrah, Warrington John M., Lattin John, Chang Jufang, Ha Helen, Haug-Kröper Martina, Doray Balraj, Gill Saar, Ruella Marco, Hayer Katharina E., Weitzman Matthew D., Green Abby M., Fluhrer Regina, Singh Nathan. Antigen glycosylation regulates efficacy of CAR T cells targeting CD19. Nature Communications 2022;13(1):3367. https://doi.org/10.1038/s41467-022-31035-7
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Papadopoulou Alkmini A., Stelzer Walter, Silber Mara, Schlosser Christine, Spitz Charlotte, Haug-Kröper Martina, Straub Tobias, Müller Stephan A., Lichtenthaler Stefan F., Muhle-Goll Claudia, Langosch Dieter, Fluhrer Regina. Helical stability of the GnTV transmembrane domain impacts on SPPL3 dependent cleavage. Scientific Reports 2022;12(1):20987. https://doi.org/10.1038/s41598-022-24772-8
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Mentrup Torben, Stumpff-Niggemann Anna Yamina, Leinung Nadja, Schlosser Christine, Schubert Katja, Wehner Rebekka, Tunger Antje, Schatz Valentin, Neubert Patrick, Gradtke Ann-Christine, Wolf Janina, Rose-John Stefan, Saftig Paul, Dalpke Alexander, Jantsch Jonathan, Schmitz Marc, Fluhrer Regina, Jacobsen Ilse D., Schröder Bernd. Phagosomal signalling of the C-type lectin receptor Dectin-1 is terminated by intramembrane proteolysis. Nature Communications 2022;13(1):1880. https://doi.org/10.1038/s41467-022-29474-3
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Bühring-Uhle C., Smit P., Negraschus A., Morath V., Goldmann U., Papadopoulou Alkmini A., Heider M., Riviere J., Götze K., Heinz L., Fluhrer Regina, Moser M., Superti-Furga G., Bassermann F., Eichner R.. SPPL3 and its substrate glycosyltransferases regulate the N-glycosylation of SLC3A2 and alter the affinities of anti-SLC3A2 immunotherapies in AML [Abstract]. Oncology Research and Treatment 2022;45(Supplement 2):95. https://doi.org/10.1159/000526456
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2020
Spitz Charlotte, Schlosser Christine, Guschtschin-Schmidt Nadja, Stelzer Walter, Menig Simon, Götz Alexander, Haug-Kröper Martina, Scharnagl Christina, Langosch Dieter, Muhle-Goll Claudia, Fluhrer Regina. Non-canonical shedding of TNFα by SPPL2a is determined by the conformational flexibility of its transmembrane helix. iScience 2020;23(12):101775. https://doi.org/10.1016/j.isci.2020.101775
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Mentrup Torben, Cabrera-Cabrera Florencia, Fluhrer Regina, Schröder Bernd. Physiological functions of SPP/SPPL intramembrane proteases. Cellular and Molecular Life Sciences 2020;77(15):2959-2979. https://doi.org/10.1007/s00018-020-03470-6
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Papadopoulou Alkmini A., Fluhrer Regina. Signalling functions of intramembrane aspartyl-proteases. Frontiers in Cardiovascular Medicine 2020;7:591787. https://doi.org/10.3389/fcvm.2020.591787
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Brugger Manuel S., Baumgartner Kathrin, Mauritz Sophie C. F., Gerlach Stefan C., Röder Florian, Schlosser Christine, Fluhrer Regina, Wixforth Achim, Westerhausen Christoph. Vibration enhanced cell growth induced by surface acoustic waves as in vitro wound healing model. PNAS 2020;117(50):31603-31613. https://doi.org/10.1073/pnas.2005203117
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2019
Mentrup Torben, Theodorou Kosta, Cabrera-Cabrera Florencia, Helbig Andreas O., Happ Kathrin, Gijbels Marion, Gradtke Ann-Christine, Rabe Björn, Fukumori Akio, Steiner Harald, Tholey Andreas, Fluhrer Regina, Donners Marjo, Schröder Bernd. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. Journal of Experimental Medicine 2019;216(4):807-830. https://doi.org/10.1084/jem.20171438
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Fluhrer Regina, Hampe Wolfgang, editors. Biochemie hoch 2 und Molekularbiologie. München: Urban & Fischer in Elsevier; 2019.
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Fluhrer Regina. Intramembrane proteases in neurodegenerative diseases. Open Access Government 2019;(23 (July 2019)):162-164.
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Fluhrer Regina. Intramembrane proteases in the immune system. Open Access Government 2019;(22 (April 2019)):72-73.
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Papadopoulou Alkmini A., Müller Stephan A, Mentrup Torben, Shmueli Merav D, Niemeyer Johannes, Haug‐Kröper Martina, von Blume Julia, Mayerhofer Artur, Feederle Regina, Schröder Bernd, Lichtenthaler Stefan F., Fluhrer Regina. Signal peptide peptidase‐like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins. EMBO reports 2019;20(3):e46451. https://doi.org/10.15252/embr.201846451
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Niemeyer Johannes, Mentrup Torben, Heidasch Ronny, Müller Stephan A, Biswas Uddipta, Meyer Rieke, Papadopoulou Alkmini A., Dederer Verena, Haug‐Kröper Martina, Adamski Vivian, Lüllmann-Rauch Renate, Bergmann Martin, Mayerhofer Artur, Saftig Paul, Wennemuth Gunther, Jessberger Rolf, Fluhrer Regina, Lichtenthaler Stefan F., Lemberg Marius K, Schröder Bernd. The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. EMBO Reports 2019;20(3):e46449. https://doi.org/10.15252/embr.201846449
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Fluhrer Regina, Schröder Bernd. What is the role of the intramembrane proteases in cancer?. Open Access Government 2019;(23 (October 2019)):184-185.
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2018
Fluhrer Regina. A unique family of intramembrane proteases. Scientia 2018;(July 4, 2018). https://doi.org/10.26320/SCIENTIA179
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Fluhrer Regina. Health report: the challenge of cleaving proteins in the membrane. Open Access Government 2018;(20 (October 2018)):38-39.
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Fluhrer Regina. Intramembrane proteases - regulators of cellular pathways. Open Access Government News 2018;(November 21, 2018).
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Lichtenthaler Stefan F., Lemberg Marius K., Fluhrer Regina. Proteolytic ectodomain shedding of membrane proteins in mammals - hardware, concepts, and recent developments. EMBO Journal 2018;37(15):e99456. https://doi.org/10.15252/embj.201899456
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2017
Jules Felix, Sauvageau Etienne, Dumaresq-Doiron Karine, Mazzaferri Javier, Haug-Kröper Martina, Fluhrer Regina, Costantino Santiago, Lefrancois Stephane. CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein. Experimental Cell Research 2017;357(1):40-50. https://doi.org/10.1016/j.yexcr.2017.04.024
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Mentrup Torben, Fluhrer Regina, Schröder Bernd. Latest emerging functions of SPP/SPPL intramembrane proteases. European Journal of Cell Biology 2017;96(5):372-382. https://doi.org/10.1016/j.ejcb.2017.03.002
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Mentrup Torben, Loock Ann-Christine, Fluhrer Regina, Schröder Bernd. Signal peptide peptidase and SPP-like proteases: possible therapeutic targets?. Biochimica et Biophysica Acta (BBA): Molecular Cell Research 2017;1864(11):2169-2182. https://doi.org/10.1016/j.bbamcr.2017.06.007
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2016
Hüttl Susann, Helfrich F., Mentrup Torben, Held S., Fukumori Akio, Steiner Harald, Saftig Paul, Fluhrer Regina, Schroder B.. Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. Biochemical Journal 2016;473(10):1405-1422. https://doi.org/10.1042/bcj20160156
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2015
Mentrup Torben, Häsler Robert, Fluhrer Regina, Saftig Paul, Schröder Bernd. A cell-based assay reveals nuclear translocation of intracellular domains released by SPPL proteases. Traffic: the international journal of intracellular transport 2015;16(8):871-892. https://doi.org/10.1111/tra.12287
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Kamp Frits, Winkler Edith, Trambauer Johannes, Ebke Amelie, Fluhrer Regina, Steiner Harald. Intramembrane proteolysis of β-amyloid precursor protein by γ-secretase is an unusually slow process. Biophysical Journal 2015;108(5):1229-1237. https://doi.org/10.1016/j.bpj.2014.12.045
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Fleck Daniel, Voss Matthias, Brankatschk Ben, Giudici Camilla, Hampel Heike, Schwenk Benjamin, Edbauer Dieter, Fukumori Akio, Steiner Harald, Kremmer Elisabeth, Haug-Kröper Martina, Rossner Moritz J., Fluhrer Regina, Willem Michael, Haass Christian. Proteolytic processing of neuregulin 1 type III by three intramembrane-cleaving proteases. Journal of Biological Chemistry 2015;291(1):318-333. https://doi.org/10.1074/jbc.m115.697995
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Kuhn Peer-Hendrik, Voss Matthias, Haug-Kröper Martina, Schröder Bernd, Schepers Ute, Bräse Stefan, Haass Christian, Lichtenthaler Stefan F., Fluhrer Regina. Secretome analysis identifies novel signal peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways. Molecular & Cellular Proteomics 2015;14(6):1584-1598. https://doi.org/10.1074/mcp.m115.048298
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2014
Fluhrer Regina. Intramembrane cleaving proteases (I-CLiPs) as guardians of shuttling proteins. Cell Cycle 2014;13(5):695-695. https://doi.org/10.4161/cc.28089
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Voss Matthias, Künzel Ulrike, Higel Fabian, Kuhn Peer‐Hendrik, Colombo Alessio, Fukumori Akio, Haug‐Kröper Martina, Klier Bärbel, Grammer Gudula, Seidl Andreas, Schröder Bernd, Obst Reinhard, Steiner Harald, Lichtenthaler Stefan F., Haass Christian, Fluhrer Regina. Shedding of glycan‐modifying enzymes by signal peptide peptidase‐like 3 (SPPL3) regulates cellular N‐glycosylation. EMBO Journal 2014;33(24):2890-2905. https://doi.org/10.15252/embj.201488375
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Schneppenheim Janna, Hüttl Susann, Kruchen Anne, Fluhrer Regina, Müller Ingo, Saftig Paul, Schneppenheim Reinhard, Martin Christa L., Schröder Bernd. Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. Biochemical and Biophysical Research Communications 2014;451(1):48-53. https://doi.org/10.1016/j.bbrc.2014.07.051
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Schneppenheim Janna, Hüttl Susann, Mentrup Torben, Lüllmann-Rauch Renate, Rothaug M., Engelke Michael, Dittmann Kai, Dressel Ralf, Araki M., Araki K., Wienands Jürgen, Fluhrer Regina, Saftig Paul, Schroder B.. The intramembrane proteases signal peptide peptidase-like 2a and 2b have distinct functions in vivo. Molecular and Cellular Biology 2014;34(8):1398-1411. https://doi.org/10.1128/mcb.00038-14
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2013
Voss Matthias, Schröder Bernd, Fluhrer Regina. Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases. Biochimica et Biophysica Acta (BBA): Biomembranes 2013;1828(12):2828-2839. https://doi.org/10.1016/j.bbamem.2013.03.033
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Poggi Marjorie, Kara Imène, Brunel Jean-Michel, Landrier Jean-François, Govers Roland, Bonardo Bernadette, Fluhrer Regina, Haass Christian, Alessi Marie-Christine, Peiretti Franck. Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling. Biochimica et Biophysica Acta (BBA): Molecular Cell Research 2013;1833(3):602-612. https://doi.org/10.1016/j.bbamcr.2012.11.009
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Bronckers Antonius LJJ, Gueneli Nur, Lüllmann-Rauch Renate, Schneppenheim Janna, Moraru Andreea P, Himmerkus Nina, Bervoets Theodore J, Fluhrer Regina, Everts Vincent, Saftig Paul, Schröder Bernd. The intramembrane protease SPPL2A is critical for tooth enamel formation. Journal of Bone and Mineral Research 2013;28(7):1622-1630. https://doi.org/10.1002/jbmr.1895
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Zahn Claudia, Kaup Matthias, Fluhrer Regina, Fuchs Hendrik. The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b. FEBS Journal 2013;280(7):1653-1663. https://doi.org/10.1111/febs.12176
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2012
Voss Matthias, Fukumori Akio, Kuhn Peer-Hendrik, Künzel Ulrike, Klier Bärbel, Grammer Gudula, Haug-Kröper Martina, Kremmer Elisabeth, Lichtenthaler Stefan F., Steiner Harald, Schröder Bernd, Haass Christian, Fluhrer Regina. Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3). Journal of Biological Chemistry 2012;287(52):43401-43409. https://doi.org/10.1074/jbc.m112.371369
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Schneppenheim Janna, Dressel Ralf, Hüttl Susann, Lüllmann-Rauch Renate, Engelke Michael, Dittmann Kai, Wienands Jürgen, Eskelinen Eeva-Liisa, Hermans-Borgmeyer Irm, Fluhrer Regina, Saftig Paul, Schröder Bernd. The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. Journal of Experimental Medicine 2012;210(1):41-58. https://doi.org/10.1084/jem.20121069
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2011
Fluhrer Regina, Kamp Frits, Grammer Gudula, Nuscher Brigitte, Steiner Harald, Beyer Klaus, Haass Christian. The nicastrin ectodomain adopts a highly thermostable structure. Biological Chemistry 2011;392(11):995-1001. https://doi.org/10.1515/bc.2011.169
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Fluhrer Regina, Martin Lucas, Klier Bärbel, Haug-Kröper Martina, Grammer Gudula, Nuscher Brigitte, Haass Christian. The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). Journal of Biological Chemistry 2011;287(7):5156-5163. https://doi.org/10.1074/jbc.m111.328104
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2010
Fukumori Akio, Fluhrer Regina, Steiner Harald, Haass Christian. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. Journal of Neuroscience 2010;30(23):7853-7862. https://doi.org/10.1523/jneurosci.1443-10.2010
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2009
Fluhrer Regina, Steiner Harald, Haass Christian. Intramembrane proteolysis by signal peptide peptidases: a comparative discussion of GXGD-type aspartyl proteases. Journal of Biological Chemistry 2009;284(21):13975-13979. https://doi.org/10.1074/jbc.r800040200
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Fluhrer Regina, Haass Christian. Intramembrane proteolysis by γ-secretase and signal peptide peptidases. In: Intracellular traffic and neurodegenerative disorders. Berlin [u.a.]: Springer; 2009. p. 11-26. https://doi.org/10.1007/978-3-540-87941-1_2
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Martin Lucas, Fluhrer Regina, Haass Christian. Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis. Journal of Biological Chemistry 2009;284(9):5662-5670. https://doi.org/10.1074/jbc.m807485200
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2008
Steiner Harald, Fluhrer Regina, Haass Christian. Intramembrane proteolysis by γ-secretase. Journal of Biological Chemistry 2008;283(44):29627-29631. https://doi.org/10.1074/jbc.r800010200
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Fluhrer Regina, Fukumori Akio, Martin Lucas, Grammer Gudula, Haug-Kröper Martina, Klier Bärbel, Winkler Edith, Kremmer Elisabeth, Condron Margaret M., Teplow David B., Steiner Harald, Haass Christian. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. Journal of Biological Chemistry 2008;283(44):30121-30128. https://doi.org/10.1074/jbc.m806092200
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2007
Prager Kai, Wang-Eckhardt Lihua, Fluhrer Regina, Killick Richard, Barth Esther, Hampel Heike, Haass Christian, Walter Jochen. A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling. Journal of Biological Chemistry 2007;282(19):14083-14093. https://doi.org/10.1074/jbc.m608437200
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Martin Lucas, Fluhrer Regina, Reiss Karina, Kremmer Elisabeth, Saftig Paul, Haass Christian. Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. Journal of Biological Chemistry 2007;283(3):1644-1652. https://doi.org/10.1074/jbc.m706661200
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Fluhrer Regina, Haass Christian. Signal peptide peptidases and gamma-secretase: cousins of the same protease family?. Neurodegenerative Diseases 2007;4(2-3):112-116. https://doi.org/10.1159/000101835
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2006
Fluhrer Regina, Grammer Gudula, Israel Lars, Condron Margaret M., Haffner Christof, Friedmann Elena, Böhland Claudia, Imhof Axel, Martoglio Bruno, Teplow David B., Haass Christian. A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b. Nature Cell Biology 2006;8(8):894-896. https://doi.org/10.1038/ncb1450
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2005
Krawitz Peter, Haffner Christof, Fluhrer Regina, Steiner Harald, Schmid Bettina, Haass Christian. Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3. Journal of Biological Chemistry 2005;280(47):39515-39523. https://doi.org/10.1074/jbc.m501645200
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2003
Fluhrer Regina, Multhaup Gerd, Schlicksupp Andrea, Okochi Masayasu, Takeda Masatoshi, Lammich Sven, Willem Michael, Westmeyer Gil, Bode Wolfram, Walter Jochen, Haass Christian. Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. Journal of Biological Chemistry 2003;278(8):5531-5538. https://doi.org/10.1074/jbc.m211485200
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Fluhrer Regina, Friedlein Arno, Haass Christian, Walter Jochen. Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis. Journal of Biological Chemistry 2003;279(3):1585-1593. https://doi.org/10.1074/jbc.m306653200
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Fluhrer Regina. Zwei neuartige Aspartylproteasen BACE-1 und BACE-2: Charakterisierung und Vergleich der katalytischen Spezifitäten bei der Proteolyse des Alzheimer-β-Amyloid-Vorläufer-Proteins. München: Ludwig-Maximilians-Universität München; 2003.
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München, Univ., Diss., 2003

2002
Fluhrer Regina, Capell Anja, Westmeyer Gil, Willem Michael, Hartung Bianka, Condron Margaret M., Teplow David B., Haass Christian, Walter Jochen. A non-amyloidogenic function of BACE-2 in the secretory pathway. Journal of Neurochemistry 2002;81(5):1011-1020. https://doi.org/10.1046/j.1471-4159.2002.00908.x
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Capell Anja, Meyn Liane, Fluhrer Regina, Teplow David B., Walter Jochen, Haass Christian. Apical sorting of beta-secretase limits amyloid beta-peptide production. Journal of Biological Chemistry 2002;277(7):5637-5643. https://doi.org/10.1074/jbc.m109119200
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2001
Walter Jochen, Fluhrer Regina, Hartung Bianka, Willem Michael, Kaether Christoph, Capell Anja, Lammich Sven, Multhaup Gerd, Haass Christian. Phosphorylation regulates intracellular trafficking of beta-secretase. Journal of Biological Chemistry 2001;276(18):14634-14641. https://doi.org/10.1074/jbc.m011116200
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