Priv. Doz. Dr. Regina Fluhrer
Group Leader
PD Dr. Fluhrer is group leader at the Adolf Butenandt Institute at the LMU
German Center for Neurodegenerative Diseases (DZNE)
Schillerstraße 44
80336 Munich
regina.fluhrer(at)dzne.de
+49 (0) 89 / 2180-75487
+49 (0) 89 / 2180-75464 (Lab)
+49 (0) 89 / 2180-75415
More information
Areas of investigation/research focus
Intramembrane cleaving proteases (ICliPs) are required for reverse signaling and membrane protein degradation. One class of these proteases is represented by the GxGD-type aspartyl proteases (Fig 1). GxGD describes a novel signature sequence, which discriminates these proteases from conventional aspartyl-proteases. Members of the class of the GxGD-type aspartyl proteases are the Alzheimer's disease related presenilins (PS), the signal peptide peptidase (SPP) and their homologues (SPPLs), as well as the bacterial type IV prepilin peptidases (TFPP).
- Figure 1: Model depicting the homologies of the active centre between Presenilin and the SPP/SPPL-protease family.
Very recently, we were able to identify two substrates (TNFα and Bri2) for regulated intramembrane proteolysis (RIP) , which are cleaved within their transmembrane domain by SPPL2b, one member of the SPP/SPPL family (Fig. 2). An initial substrate shedding greatly supports the subsequent intramembrane cleavage by SPPL2b, but structural elements within the substrates transmembranedomain and juxtamembranedomains are additionally required to define a substrate.
- Fig. 1: Schematic representation of the regulated intramembrane proteolysis of TNFα and Bri2.
The research project associated to the DZNE aims to understand the homologies and differences between the PS-family and the SPP/SPPL-family and test potential therapeutic agents against Alzheimer’s disease on cross reactivity with SPP/SPPL-proteases.
Publications
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).
Fluhrer R, Martin L, Klier B, Haug-Kröper M, Grammer G, Nuscher B, Haass C. J Biol Chem. 2012 Feb 10;287(7):5156-63. Epub 2011 Dec 22.
Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis.
A. Fukumori, R. Fluhrer, H. Steiner and C. Haass, J Neurosci. 2010 Jun 9;30(23):7853-62.
Intramembrane Proteolysis by γ-Secretase and Signal Peptide Peptidases
R. Fluhrer and C. Haass, in: Research and Perspectives in Alzheimer's Disease - Intracellular Traffic and Neurodegenerative Disorders, Springer Verlag, Berlin Heidelberg 2009
Intramembrane Proteolysis by Signal Peptide Peptidases – A Comparative Discussion of GxGD-Type Aspartyl Proteases
R. Fluhrer*, H. Steiner, and C. Haass*, J Biol Chem. 2009 May 22;284(21):13975-9
*corresponding authors
Substrate Requirements for SPPL2b Dependent Regulated Intramembrane Proteolysis
L. Martin, R. Fluhrer* and C. Haass*, J Biol Chem. 2009;284(9):5662-70.
*corresponding authors
Intramembrane Proteolysis by γ-secretase
H. Steiner, R. Fluhrer and C. Haass, J Biol Chem. 2008 Oct 31;283(44):29627-31.
Intramembrane Proteolysis of GxGD-type Aspartyl Proteases is slowed by a Familial Alzheimer Disease-like Mutation
R. Fluhrer, A. Fukumori, L. Martin, G. Grammer, M. Haug-Kröper, B. Klier, E. Winkler, E. Kremmer, MM, Condron, DB. Teplow, H. Steiner and C. Haass, J Biol Chem. 2008;283(44):30121-8.
Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/b
L. Martin*, R. Fluhrer*, K.Reiss, E. Kremmer, P.Saftig and C. Haass, J Biol Chem. 2008;283(3):1644-52
*authors contributed equally
Signal Peptide Peptidases and γ-Secretase: Cousins of the Same Protease Family?
R. Fluhrer and C. Haass, Neurodegener Dis. 2007;4(2-3):112-116.
A structural switch of presenilin 1 by glycogen synthase kinase 3b-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling
K. Prager, L. Wang-Eckhardt, R.Fluhrer, R. Killick, E. Barth, H. Hampel, C. Haass and J. Walter, J Biol Chem. 2007;282(19):14083-93
A y-secretase-like intramembrane cleavage of TNFa by the GxGD aspartyl protease SPPL2b
R. Fluhrer, G. Grammer, L. Israel, MM. Condron, C.Haffner, E. Friedmann, C. Böhland, A. Imhof, B. Martoglio, DB. Teplow and C. Haass, Nat Cell Biol. 2006;8(8):894-6
Differential Localization and Identification of a Critical Aspartate Suggest non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3
P. Krawitz*, C. Haffner*, R. Fluhrer*, H. Steiner, B. Schmid and C. Haass, J Biol Chem. 2005;280(47):39515-23
*authors contributed equally
Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates its Proteolytic Processing and the Progression of Apoptosis
R. Fluhrer, A. Friedlein, C. Haass and J. Walter, J Biol Chem. 2004; 279(3): 1585-93
Identification of a β-Secretase Activity, Which Truncates Amyloid β-Peptide after Its Presenilin-dependent Generation.
R. Fluhrer*, G. Multhaup*, A. Schlicksupp, M. Okochi, M. Takeda, S. Lammich, M. Willem, G. Westmeyer, W. Bode, J. Walter and C. Haass, J Biol Chem. 2003;278(8):5531-38
*authors contributed equally
A Non-Amyloidogenic Function of BACE-2 in the Secretory Pathway
R. Fluhrer, A. Capell, G. Westmeyer, M. Willem, B. Hartung, MM. Condron, DB. Teplow, C. Haass and J. Walter, J Neurochem. 2002;81(5):1011-20.
Apical Sorting of β-Secretase Limits Amyloid b-Peptide Production
A. Capell, L. Meyn, R. Fluhrer, DB. Teplow, J. Walter and C. Haass, J Biol Chem. 2002;277(7):5637-43
Phosphorylation Regulates Intracellular Trafficking of β-Secretase
J. Walter, R. Fluhrer, B. Hartung, M. Willem, C. Kaether, A. Capell, S. Lammich, G. Multhaup and C. Haass, J Biol Chem. 2001; 276 (18): 14634-41