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Genomes and Genes | Harald SteinerSummaryAffiliation: University of Munich Country: Germany Publications
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Publications
Pore-forming scissors? A first structural glimpse of gamma-secretaseHarald Steiner
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
Trends Biochem Sci 31:491-3. 2006..It indicates a spherical transmembrane particle with an interior chamber that, presumably, accommodates its catalytic residues, and two openings that might be exit sites for the cleavage products...- The catalytic core of gamma-secretase: presenilin revisitedHarald Steiner
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Schil lerstr 44, Ludwig Maximilians University, 80336 Munich, Germany
Curr Alzheimer Res 5:147-57. 2008..This review recapitulates the findings that led to this conclusion as well as the further progress made on the function of PS as gamma-secretase since then... 
Chemical cross-linking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1Harald Steiner
Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 283:34677-86. 2008....- Intramembrane proteolysis by gamma-secretaseHarald Steiner
Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 283:29627-31. 2008..Modulators of gamma-secretase, which selectively affect the production of the pathological 42-amino acid Abeta, do not inhibit Notch signaling... - Gamma-secretase complex assembly within the early secretory pathwayAnja Capell
Adolf Butenandt Institut, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians Universitat, Schillerstrasse 44, 80336 Munich, Germany
J Biol Chem 280:6471-8. 2005.... - Reconstitution of gamma-secretase activityDieter Edbauer
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
Nat Cell Biol 5:486-8. 2003..Thus, the biological activity of gamma-secretase is reconstituted by the co-expression of human PS, Nct, APH-1 and PEN-2 in yeast... - The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretaseAya Yamasaki
Laboratory for Alzheimer s and Parkinson s Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Munich, Germany
J Neurosci 26:3821-8. 2006..Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of gamma-secretase... - Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1Keiro Shirotani
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Neurochem 89:1520-7. 2004..Moreover, binding of the latter two complex partners critically depends on the integrity of the Nct ectodomain... - Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domainAnja Capell
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 278:52519-23. 2003..We identified the N-terminal region of the NCT TMD as a functionally important entity of NCT. These data thus demonstrate that NCT interacts with other gamma-secretase complex components via its TMD... - Presenilin-1 affects trafficking and processing of betaAPP and is targeted in a complex with nicastrin to the plasma membraneChristoph Kaether
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Cell Biol 158:551-61. 2002..Our data suggest that PS is targeted as a biologically active complex with Nct through the secretory pathway to the cell surface and suggest a dual function of PS in gamma-secretase processing and in trafficking... - Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptideSven Lammich
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 277:44754-9. 2002..The dual cleavage mechanism is required for nuclear signaling as well as removal of remaining transmembrane domains, a general function of PS in membrane protein metabolism... - Identification of distinct gamma-secretase complexes with different APH-1 variantsKeiro Shirotani
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 279:41340-5. 2004..Taken together, our results suggest that, dependent on the tissue expression of the individual subunits, six distinct gamma-secretase complexes composed of the known subunits can exist in human cells... - Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3Peter Krawitz
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
J Biol Chem 280:39515-23. 2005..Furthermore, SPPL2b is shown to be the first member of the SPP/PSH/SPPL family that is not located within the ER but in endosomal/lysosomal vesicles... - The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activityChristoph Kaether
Laboratory for Alzheimer s and Parkinson s Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians Universitat, Munchen, Germany
EMBO J 23:4738-48. 2004..Deletion of the retention signal results in the release of PS1 from the ER and the assembly of a nonfunctional gamma-secretase complex, suggesting that at least a part of the retention motif may also be required for the function of PS1... - PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrinHarald Steiner
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 277:39062-5. 2002..We conclude that PEN-2 is an integral gamma-secretase complex component and that gamma-secretase complex components are expressed in a coordinated manner... 
Requirement for small side chain residues within the GxGD-motif of presenilin for gamma-secretase substrate cleavageBlanca Isabel Pérez-Revuelta
Deutsches Zentrum für Neurodegenerative Erkrankungen DZNE and Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, Munchen, Germany
J Neurochem 112:940-50. 2010..These findings broaden our understanding of gamma-secretase substrate recognition and cleavage, which may prove crucial for therapeutic targeting of the enzyme...- Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of presenilin fragmentsStefan Prokop
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, Munich, Germany
J Neurochem 94:57-62. 2005..Taken together, our data suggest that the PS-subunit stabilizing function of PEN-2 depends on length and overall sequence of its C-terminal domain... - Beta-amyloid precursor protein mutants respond to gamma-secretase modulatorsRichard M Page
German Center for Neurodegenerative Diseases DZNE and Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 285:17798-810. 2010.... - Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1Christoph Kaether
Laboratory for Alzheimer s and Parkinson s Disease Research, Department of Biochemistry, Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Ludwig Maximilians Universitat, München 80336, Germany
EMBO Rep 8:743-8. 2007..To our knowledge, Rer1 is the first identified interaction partner of mammalian transmembrane-based retention/retrieval signals... - Purification, pharmacological modulation, and biochemical characterization of interactors of endogenous human gamma-secretaseEdith Winkler
Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
Biochemistry 48:1183-97. 2009..In addition, we provide evidence that the copurifying proteins identified are unlikely to be part of the active gamma-secretase enzyme... - Pathological activity of familial Alzheimer's disease-associated mutant presenilin can be executed by six different gamma-secretase complexesKeiro Shirotani
Munich Center for Integrated Protein Science and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, Schillerstr 44, Munich, Germany
Neurobiol Dis 27:102-7. 2007.... - Requirement of PEN-2 for stabilization of the presenilin N-/C-terminal fragment heterodimer within the gamma-secretase complexStefan Prokop
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians-University, 80336 Munich, Germany
J Biol Chem 279:23255-61. 2004..This function critically depends on the PEN-2 C terminus. Moreover, our data show that PEN-2 is generally required for gamma-secretase complex maturation independent of its activity in PS1 endoproteolysis... - Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutationRegina Fluhrer
Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, Munich 80336, Germany
J Biol Chem 283:30121-8. 2008..Thus, the PS1 G384A mutation causes a selective loss of function by slowing the processing pathway leading to the benign Abeta40... - Gamma-secretase activity is associated with a conformational change of nicastrinKeiro Shirotani
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
J Biol Chem 278:16474-7. 2003..Furthermore, the conformational alteration did not occur in the absence of PS. Our data thus suggest that gamma-secretase function critically depends on the structural "activation" of Nct... - Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 productionTobias Moehlmann
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
Proc Natl Acad Sci U S A 99:8025-30. 2002..Finally, we show that PS1 L166 mutants affect the generation of NICD and AICD in a similar manner, supporting the concept that S3 protease and S3-like gamma-secretase cleavages are mediated by identical proteolytic activities... - Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1Dieter Edbauer
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstr 44, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 279:37311-5. 2004..We conclude that cooperative effects may stabilize a trim-eric complex of APH-1a G122D together with PS1 and NCT. Upon successful complex assembly, the GXXXG motif becomes dispensable for gamma-secretase activity... - The Nicastrin ectodomain adopts a highly thermostable structureRegina Fluhrer
Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
Biol Chem 392:995-1001. 2011..These findings provide evidence to further support the hypothesis that Nicastrin may share evolutionary conserved properties with the aminopeptidase and the transferrin receptor family... - Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formationDieter Edbauer
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
Proc Natl Acad Sci U S A 99:8666-71. 2002..Based on these findings we conclude that Nct and PS regulate each other and determine gamma-secretase function via complex formation... - Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3)Matthias Voss
Adolf Butenandt Institute for Biochemistry, Ludwig Maximilians University Munich, 80336 Munich, Germany
J Biol Chem 287:43401-9. 2012..Thus, human SPPL3 is the first GxGD-type aspartyl protease shown to be capable of acting like a sheddase, similar to members of the rhomboid family, which belong to the class of intramembrane-cleaving serine proteases... - Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thicknessEdith Winkler
Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University Munich, Schillerstrasse 44, 80336 Munich, Germany
J Biol Chem 287:21326-34. 2012..Our data demonstrate an effective modulation of γ-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic Aβ(42/43) species... - Attenuated Abeta42 responses to low potency gamma-secretase modulators can be overcome for many pathogenic presenilin mutants by second-generation compoundsBenedikt Kretner
DZNE German Center for Neurodegenerative Diseases, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 286:15240-51. 2011.... - Loss of PAFAH1B2 reduces amyloid-β generation by promoting the degradation of amyloid precursor protein C-terminal fragmentsRichard M Page
Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, 80336 Munich, Germany
J Neurosci 32:18204-14. 2012..In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering Aβ... - Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteasesChristian Haass
Adolf Butenandt Institute, Dept of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University Munich, Schillerstr 44, 80336 Munich, Germany
Trends Cell Biol 12:556-62. 2002.... - Intramembrane proteolysis by signal peptide peptidases: a comparative discussion of GXGD-type aspartyl proteasesRegina Fluhrer
Deutsches Zentrum für Neurodegenerative Erkrankungen DZNE and Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, Munich, 80336 Munich, Germany
J Biol Chem 284:13975-9. 2009..We then compare these properties with those of gamma-secretase and discuss common mechanisms but also point out a number of substantial differences... - Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulationRichard M Page
Center for Integrated Protein Science Munich and Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 283:677-83. 2008..Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators... - Novel γ-secretase enzyme modulators directly target presenilin proteinAmelie Ebke
Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, 80336 Munich, Germany
J Biol Chem 286:37181-6. 2011.... - Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanismsStefan Mitterreiter
German Center for Neurodegenerative Diseases Munich and Adolf Butenandt Institute, Biochemistry, University of Munich, 80336 Munich, Germany
J Neurosci 30:8974-83. 2010..In addition to Alzheimer's disease, compounds with dual properties may also be useful for drug development targeting other membrane proteins... - Uncovering gamma-secretaseHarald Steiner
Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
Curr Alzheimer Res 1:175-81. 2004..The other components are required for assembly, stabilization and maturation of the complex and NCT may be involved in the recognition of gamma-secretase substrates... - Regulated intramembrane proteolysis--lessons from amyloid precursor protein processingStefan F Lichtenthaler
DZNE German Center for Neurodegenerative Diseases, Adolf Butenandt Institute, Biochemistry, Ludwig Maximilians University, Munich, Germany
J Neurochem 117:779-96. 2011..Focusing on APP as the best-studied RIP substrate, this review describes the function and mechanism of the APP RIP proteases with the goal to elucidate cellular mechanisms and common principles of the RIP process in general... - Sheddases and intramembrane-cleaving proteases: RIPpers of the membrane. Symposium on regulated intramembrane proteolysisStefan F Lichtenthaler
Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory of Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, Schillerstrasse 44, 80336 Munich, Germany
EMBO Rep 8:537-41. 2007 - Assembly, trafficking and function of gamma-secretaseChristoph Kaether
Laboratory for Alzheimer s and Parkinson s Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany
Neurodegener Dis 3:275-83. 2006..Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for gamma-secretase complex assembly... - Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD)Dieter Edbauer
Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Adolf Butenandt Institute, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
J Biol Chem 277:13389-93. 2002..Therefore our data demonstrate that IDE, which is one of the proteases implicated in the removal of extracellular Abeta, also removes the cytoplasmic product of gamma-secretase cleaved APP... - A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafishAndrea Geling
Zebrafish Neurogenetics Junior Research Group, Institute for Virology, Technical University Munich, Trogerstrasse, Germany
EMBO Rep 3:688-94. 2002.... - Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1Masayasu Okochi
Department of Post Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, 565 0871 Osaka, Japan
EMBO J 21:5408-16. 2002..Considering these similarities between intramembranous processing of Notch and betaAPP, we conclude that these proteins are cleaved by a common mechanism utilizing the same protease, i.e. PS/gamma-secretase... - Active gamma-secretase complexes contain only one of each componentToru Sato
Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
J Biol Chem 282:33985-93. 2007..Taken together, these results demonstrate that the stoichiometry of gamma-components presenilin:Pen-2:nicastrin:Aph-1 is 1:1:1:1... - Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulatorsRajeshwar Narlawar
, Darmstadt University of Technology, Petersenstrasse 22, D-64287 Darmstadt, Germany
J Med Chem 49:7588-91. 2006..Several compounds (e.g., 9p, 11f) caused selective reduction of Abeta42 and an increase of Abeta38. The most active compounds displayed activities in the low micromolar range and no effect on the gamma-secretase cleavage at the e-site... - Secretion of the Notch-1 Abeta-like peptide during Notch signalingMasayasu Okochi
Department of Post Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, Osaka 565 0871, Japan
J Biol Chem 281:7890-8. 2006..We anticipate that this study will open the door to searches for markers of RIP signaling and surrogate markers for Abeta42 production... - SorLA signaling by regulated intramembrane proteolysisChristopher Bohm
University Medical Center Hamburg Eppendorf, Center of Experimental Medicine, Department of Biochemistry and Molecular Biology II Molecular Cell Biology, Martinistrasse 52, D 20246 Hamburg, Germany
J Biol Chem 281:14547-53. 2006..In a reporter gene assay the cytoplasmic domain of SorLA acted as a transcriptional activator indicating that SorLA might directly regulate transcription after activation by gamma-secretase... - N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretaseRajeshwar Narlawar
Clemens Schöpf Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr 22, D 64287 Darmstadt, Germany
Bioorg Med Chem Lett 17:176-82. 2007..The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the gamma-secretase cleavage at the epsilon-site...