Prof. Dr. Harald Steiner

Lebenslauf

Name Prof. Dr. Harald Steiner
Geburtsort Stuttgart
Geburtsdatum 05.02.1965
   
seit 2007 apl. Professor der Biochemie an der LMU München 
seit 2007 Akademischer Oberrat am Adolf-Butenandt-Institut der LMU München
2006 Forschungspreis der Hans und Ilse Breuer-Stiftung
2003-2007 Akademischer Rat am Adolf-Butenandt-Institut der LMU München
2002 Habilitation an der LMU München
1999-2003 Wissenschaftlicher Assistent am Adolf-Butenandt-Institut der LMU München
1996-1999 Wissenschaftlicher Mitarbeiter („Postdoc“) am ZI Mannheim, Abteilung Molekularbiologie, Universität Heidelberg
1996 Promotion (Dr. rer nat.) an der LMU München
1992 Studienabschluss (Dipl.-Chem.) an der Universität Stuttgart
 

Projektbeschreibung

Die g-Sekretase ist eine der beiden Proteasen, die für die Entstehung des Alzheimer-verursachenden Amyloid b-Peptids (Ab) verantwortlich sind. Ein genaues Verständnis der Ab Entstehung ist von entscheidender Bedeutung, um die Krankheit therapeutisch anzugehen. Der Alzheimer Forschungspreis der Hans und Ilse Breuer-Stiftung unterstützt unsere Forschungsaktivitäten in der tiefgreifenden funktionellen und strukturellen Charakterisierung der g-Sekretase in wesentlichem Maße. Dieses ehrgeizige Projekt konzentriert sich auf die Reinigung der g-Sekretase und die Analyse ihrer molekularen Architektur, auf die Rolle von modulatorisch-wirkenden Interaktoren der g-Sekretase, wie CD147 und TMP21, auf die Identifizierung zusätzlicher g-Sekretase Modulatoren, auf die Identifizierung und Charakterisierung von g-Sekretase Substrat- und Modulator-Bindungsstellen, sowie auf Struktur-Funktions-Analysen der einzelnen g-Sekretase Untereinheiten.

 

Ausgewählte Publikationen

Original articles

1. Wieland, J., Nitsche, A.M., Strayle, J., Steiner, H. & Rudolph, H.K. (1995). The PMR2 gene cluster encodes functionally isoforms of a putative Na+-pump in the yeast plasma membrane. EMBO J. 14, 3870-3882.

2. Steiner, H., Zollner, A., Haid, A., Neupert, W. & Lill, R (1995). Biogenesis of mitochondrial heme lyases in yeast: Import and folding in the intermembrane space. J. Biol. Chem. 270, 22842-22849.

3. Kispal, G., Steiner, H., Court, D.A., Rolinski, B. & Lill, R. (1996). Mitochondrial and cytosolic branched-chain amino acid transaminases from yeast, homologs of the myc oncogene-regulated Eca39 protein. J. Biol. Chem. 271, 24458-24464.

4. Steiner, H., Kispal, G., Zollner, A., Haid, A., Neupert, W. & Lill, R. (1996). Heme binding to a conserved Cys-Pro-Val motif is crucial for the catalytic function of mitochondrial heme lyases. J. Biol. Chem. 271, 32605-32611.

5. Court, D.A., Nargang, F.E., Steiner, H., Hodges, R.S., Neupert, W. & Lill, R. (1996). Role of the intermembrane-space domain of the preprotein receptor Tom22 in protein import into mitochondria. Mol. Cell. Biol. 16, 4035-4042.

6. Wild-Bode, C., Yamazaki, T., Capell, A., Leimer, U., Steiner, H., Ihara, Y. & Haass, C. (1997). Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J. Biol. Chem. 272, 16085-16088.

7. Steiner, H., Capell, A., Pesold, B., Citron, M., Kloetzel, P.M., Selkoe, D.J., Romig, H., Mendla, K. & Haass, C. (1998). Expression of Alzheimer's disease associated presenilin-1 is controlled by proteolytic degradation and complex formation. J. Biol. Chem. 273, 32322-32331.

8. Steiner, H., Romig, H., Grim, M.G., Philipp, U., Pesold, B., Citron, M., Baumeister, R. & Haass, C. (1999). The biological and pathological function of the presenilin-1 ∆exon9 mutation is independent of its defect to undergo proteolytic processing, J. Biol. Chem. 274, 7615-7618.

9. Steiner, H., Duff, K., Capell, A., Romig, H., Grim, M.G., Lincoln, S., Hardy, J., Yu, X., Picciano, M., Fechteler, K., Citron, M., Kopan, R., Pesold, B., Keck, S., Baader, M., Tomita, T., Iwatsubo, T. & Haass, C. (1999) A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and Notch signaling. J. Biol. Chem. 274, 28669-28673.

10. Steiner, H., Romig, H., Pesold, B., Baader, M., Citron, M., Loetscher, H., Jacobsen, H. & Haass, C. (1999). Amyloidogenic function of Alzheimer's disease associated presenilin-1 in the absence of endoproteolysis. Biochemistry 38, 14600-14605.

11. Steiner, H., Pesold, B. & Haass, C. (1999). An in vivo assay for the identification of target proteases which cleave membrane-associated substrates. FEBS Lett. 463, 245-249.

12. Capell, A., Steiner, H., Romig, H., Keck, S., Baader, M., Grim, M.G., Baumeister, R. & Haass, C. (2000). Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. Nature Cell Biol., 2, 205-211.

13. Capell, A., Steiner, H., Willem, M., Kaiser, H., Meyer, C., Walter, J., Lammich, S., Multhaup, G. & Haass, C. (2000). Maturation and propeptide cleavage of beta-secretase. J. Biol. Chem. 275, 30849-30854.

14. Kulic, L., Walter, J., Multhaup, G., Teplow, D.B., Baumeister, R., Romig, H., Capell, A., Steiner, H. & Haass, C. (2000). Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch. Proc. Natl. Acad. Sci. USA 97, 5913-5918.

15. Yu, G., Chen, F., Nishimura, M., Steiner, H., Tandon, A., Kawarai, T., Arawaka, S., Supala, A., Song, Y.Q., Rogaeva, E., Holmes, E., Zhang, D.M., Milman, P., Fraser, P.E., Haass, C. & St George-Hyslop, P. (2000) Mutation of conserved aspartates affects maturation of both aspartate mutant and endogenous presenilin 1 and presenilin 2 complexes. J. Biol. Chem. 275, 27348-27353.

16. Steiner, H., Kostka, M., Romig, H., Basset, G., Pesold, B., Hardy, J., Capell, A., Meyn, L., Grim, M.G., Baumeister, R., Fechteler, K. & Haass, C. (2000) Glycine 384 is required for presenilin-1 function and is conserved in bacterial polytopic aspartyl proteases. Nature Cell Biol., 2, 848-851.

17. Okochi, M., Eimer, S., Böttcher, A., Baumeister, R., Romig, H., Walter, J., Capell, A., Steiner, H. & Haass, C. (2000) A loss of function mutant of the presenilin homologue sel-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increased A-beta42 generation in human cells. J. Biol. Chem., 275, 40925-40932.

18. Steiner, H., Revesz, T., Neumann, M., Romig, H., Grim, M.G, Pesold, P., Kretzschmar, H.A., Hardy, A., Holton, J.L., Baumeister, R., Houlden, H. & Haass, C. (2001) A pathogenic presenilin-1 deletion causes aberrant A-beta42 production in the absence of congophilic amyloid plaques. J. Biol. Chem. 276, 7233-7239.

19. Steiner, H., Winkler, E., Shearman, M.S., Prywes, R. & Haass, C. (2001). Endoproteolysis of the ER stress transducer ATF6 in the presence of functionally inactive presenilins. Neurobiol Dis. 8, 717-722.

20. Sastre, M., Steiner, H., Fuchs, K., Capell, A., Multhaup, G., Condron, M.M., Teplow, D.B., & Haass, C. (2001). Presenilin dependent gamma-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep. 2, 835-841.

21. Edbauer, D., Willem, M., Lammich, S., Steiner, H. & Haass, C. (2002) Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). J. Biol. Chem. 277, 13389-13393.

22. Moehlmann, T., Winkler, E., Xia, X., Edbauer, D., Murrell, J., Capell, A., Kaether, C., Zheng, H., Ghetti, B., Haass, C. & Steiner, H. (2002) Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on A-beta42 production. Proc. Natl. Acad. Sci. USA 99, 8025-8030.

23. Edbauer, D., Winkler, E., Haass, C. & Steiner, H. (2002) Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation. Proc. Natl. Acad. Sci. USA 99, 8666-8671.

24. Geling, A., Steiner, H., Willem, M., Bally-Cuif, L. & Haass, C. (2002) A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish. EMBO Rep. 3, 688-694.

25. Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H. & Haass C. (2002) Presenilin-1 affects trafficking and processing of beta-APP and is targeted in a complex with nicastrin to the plasma membrane. J. Cell Biol. 158, 551-561.

26. Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M. & Haass, C. (2002) PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem., 277, 39062-39065.

27. Lammich, S., Okochi, M., Takeda, M., Kaether, C., Capell, A., Zimmer, A.K., Edbauer, D., Walter, J., Steiner, H. & Haass, C. (2002) Presenilin dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an A-beta-like peptide. J. Biol. Chem., 277, 44754-44759.

28. Okochi, M., Steiner, H., Fukumori, A., Tanii, H., Tomita, T., Tanaka, T., Iwatsubo, T., Kudo, T., Takeda, M. & Haass, C. (2002) Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J., 21, 5408-5416.

29. Edbauer, D., Winkler, E., Regula, J.T., Pesold, B., Steiner, H. & Haass, C. (2003) Reconstitution of gamma-secretase activity. Nature Cell Biol., 5, 486-490.

30. Shirotani, K., Edbauer, D., Capell, A., Steiner, H. & Haass, C. (2003) gamma-Secretase activity is associated with a conformational change of nicastrin. J. Biol. Chem., 278, 16474-16744.

31. Capell, A., Kaether, C., Edbauer, D., Shirotani, K., Merkl, S., Steiner, H. & Haass, C. (2003) Nicastrin interacts with gamma-secretase complex components via the N-terminal part of its transmembrane domain. J. Biol. Chem., 52519-52523.

32. Shirotani, K., Edbauer, D., Kostka, M., Steiner, H. & Haass, C. (2004) Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin – identification of nicastrin mutants which selectively interact with APH-1. J. Neurochem., 89, 1520-1527.

33. Prokop, S., Shirotani, K., Edbauer, D., Haass, C. & Steiner, H. (2004) Requirement of PEN-2 for the stabilization of the presenilin NTF/CTF heterodimer within the gamma-secretase complex. J. Biol. Chem., 279, 23255-23261.

34. Edbauer, D., Kaether, C., Steiner, H. & Haass, C. (2004) Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1. J. Biol. Chem., 279, 37311-37315.

35. Shirotani, K., Edbauer, D., Prokop, S., Haass, C. & Steiner, H. (2004) Identification of distinct gamma-secretase complexes with different APH-1 variants. J. Biol. Chem., 279, 41340-41345.

36. Kaether, C., Capell, A., Edbauer, D., Winkler, E., Novak, B., Steiner, H. & Haass, C. (2004) The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. EMBO J., 23, 4738-4748.

37. Capell, A., Beher, D., Prokop, S., Steiner, H., Kaether, C., Shearman, M.S. & Haass, C. (2005) g-Secretase complex assembly within the early secretory pathway interacts. J. Biol. Chem., 280, 6471-6478.

38. Prokop, S., Haass, C. & Steiner, H. (2005) Length and overall sequence of the PEN-2 C-terminal domain determines its function in the stabilization of the presenilin fragments. J. Neurochem., 94, 57-62.

39. Krawitz, P., Haffner, C., Fluhrer, R., Steiner, H., Schmid, B. & Haass, C. (2005) Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3. J. Biol. Chem., 280, 39515-39523.

40. Okochi, M., Fukumori, A., Jiang, J., Itoh, N., Kimura, R., Steiner, H., Haass, C., Tagami, S. & Takeda, M. (2006) Secretion of the Notch-1 A-beta-like peptide during Notch signaling. J. Biol. Chem., 281, 7890-7898.

41. Yamasaki, A., Eimer, S., Okochi, M., Smialowska, A., Kaether, C., Baumeister, R., Haass, C. & Steiner, H. (2006) The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. J. Neurosci., 26, 3821-3828.

42. Bohm, C., Seibel, N.M., Henkel, B., Steiner, H., Haass, C. & Hampe, W. (2006) SorLA signaling by regulated intramembrane proteolysis. J. Biol. Chem., 281, 14547-14553.

43. Narlawar, R., Pérez-Revuelta, B.I., Haass, C., Steiner, H., Schmidt, B. & Baumann, K. (2006) Scaffold of the cyclooxygenase-2 (COX-2) inhibitor carprofen provides Alzheimer gamma-secretase modulators. J. Med. Chem., 49, 7588-7591.

44. Narlawar, R., Pérez-Revuelta, B.I., Baumann, K., Schubenel, R., Haass, C., Steiner, H. & Schmidt, B. (2007) N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase. Bioorg. Med. Chem. Lett., 17, 176-182.

45. Shirotani, K., Tomioka, M., Kremmer, E., Haass, C. & Steiner, H. (2007) Pathological activity of familial Alzheimer´s disease-associated mutant presenilin can be executed by six different gamma-secretase complexes. Neurobiol. Dis., 27, 102-107.

46. Kaether, C., Scheuermann, A., Fassler, M., Zilow, S., Shirotani, K., Valkova, C., Novak, B., Kacmar, S., Steiner, H. & Haass, C. (2007) ER-retention of the gamma-secretase complex component Pen2 by Rer1. EMBO Rep., 8, 743-748.

47. Sato, T., Diehl, T.S., Narayanan, S., Funamoto, S., Ihara, Y., De Strooper, B., Steiner, H., Haass, C. & Wolfe, M.S. (2007). Active gamma-secretase complexes contain only one of each component. J. Biol. Chem., 282, 33985-33993.

48. Page, R.M., Baumann, K., Tomioka, M., Pérez-Revuelta, B.I., Fukumori, A., Jacobsen, H., Flohr, A., Luebbers, T., Ozmen, L., Steiner, H. & Haass, C. (2008) Generation of A-beta38 and A-beta42 is independently and differentially affected by FAD-associated presenilin mutations and gamma-secretase modulation. J. Biol. Chem., 283, 677-683.

49. Fluhrer, R., Fukumori, A., Martin, L., Grammer, G., Haug-Kröper, M., Klier, B., Winkler, E., Kremmer, E., Condron, M.M., Teplow, D.B., Steiner, H. & Haass, C. (2008). Intramembrane proteolysis of GxGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. J. Biol. Chem., 283, 30121-30128.

50. Steiner, H., Winkler, E. & Haass, C. (2008) Chemical crosslinking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1. J. Biol. Chem., 283, 34677-34686.

51. Winkler, E., Hobson, S., Fukumori, A., Duempelfeld, B., Luebbers, T., Baumann, K., Haass, C., Hopf, C. & Steiner, H. (2009) Purification, pharmacological modulation and biochemical characterization of interactors of endogenous human gamma-secretase. Biochemistry, 48, 1183-1197.


Reviews and Commentaries

R1. Grünberg, J., Capell, A., Leimer, U., Steiner, B., Steiner, H., Walter, J. & Haass, C. (1997). Proteolytic processing of presenilin proteins: degradation or biological activation? Alzheimer’s Research 3, 253-259.

R2. Steiner, H., Capell, A. & Haass, C. (1998). Proteolytic processing and degradation of Alzheimer's disease relevant proteins. Biochem. Soc. Trans., 27, 234-242.

R3. Steiner, H., Capell, A., Leimer, U., & Haass, C. (1999). Genes and mechanisms involved in amyloid beta-peptide generation and Alzheimer's disease. Eur. Arch. Psychiatry Clin. Neurosci., 249, 266-270.

R4. Steiner, H. & Haass, C. (2000). Alzheimer Gene: Ihre Wirkung auf die Amyloidentstehung und die Embryonalentwicklung. Einsichten 17, 10-13.

R5. Yu, G., Chen, F., Nishimura, M., Steiner, H., Tandon, A., Kawarai, T., Arawaka, S., Supala, A., Song, Y.Q., Rogaeva, E., Holmes, E., Zhang, D.M., Milman, P., Fraser, P.E., Haass, C. & St George-Hyslop, P. (2000) Mutation of conserved aspartates affects maturation of both presenilin 1 and presenilin 2 complexes. Acta Neurol. Scand. Suppl. 176, 6-11.

R6. Steiner, H. & Haass, C. (2000). Intramembrane proteolysis by presenilins. Nature Rev. Mol. Cell. Biol., 1, 217-224.

R7. Haass, C., Annaert, W., Steiner, H. & De Strooper, B. (2001) Secretases reveal their secrets: proteolysis in Alzheimer's disease. In The ELSO Gazette: e-magazine of the European Life Scientist Organization (http://www.the-elso-gazette.org/magazines/issue3/reviews/reviews1.asp), Issue 3 (3 January, 2001).

R8. Walter, J., Kaether, C., Steiner, H. & Haass, C. (2001) The Cell Biology of Alzheimer´s Disease: Uncovering the secrets of secretases. Curr. Opin. Neurobiol., 11, 585-590.

R9. Steiner, H. & Haass, C. (2001). Nuclear signaling–A common function of presenilin substrates? J. Mol. Neurosci., 17, 193-198.

R10. Haass, C. & Steiner, H. (2002). Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol., 12, 556-562.

R11. Steiner, H. (2004). Uncovering gamma-secretase. Curr. Alzheimer Res., 1, 175-181.

R12. Kaether, C., Haass, C. & Steiner, H. (2006). Assembly, Trafficking and Function of -secretase. Neurodegenerative Dis., 3, 275-283.

R13. Lichtenthaler, S.F. & Steiner, H. (2007). Sheddases and intramembrane-cleaving proteases: RIPpers of the membrane. Symposium on regulated intramembrane proteolysis. EMBO Rep., 8, 537-541.

R14. Steiner, H. (2008). The catalytic core of gamma-secretase: presenilin revisited. Curr. Alzheimer Res., 5, 147-157.

R15. Steiner, H., Fluhrer, R. & Haass, C. (2008). Intramembrane proteolysis by gamma-secretase. J. Biol. Chem., 283, 29627-29631.

R16. Fluhrer, R., Steiner, H. & Haass, C. (2009). Intramembrane proteolysis by signal peptide peptidases - similar mechanisms of GxGD-type aspartyl proteases gamma-secretase? J. Biol. Chem., 284, 13975-13979.

C1. Steiner, H. & Haass, C. (2001). Protofibrils, the unifying toxic molecule of neurodegenerative disorders? Nature Neurosci., 4, 859-860.

C2. Steiner, H., Than, M., Bode, W. & Haass, C. (2006) Pore-forming scissors? A first structural glimpse of gamma-secretase. Trends Biochem. Sci., 31, 491-493.


Book chapters

B1. Lill, R., Kispal, G., Künkele, K.-P., Mayer, A., Risse, B., Steiner, H., Heckmeyer, P., van der Klei, I. & Court, D.A. (1996) Protein transport into and across the mitochondrial outer membrane: Recognition, insertion and translocation of preproteins. In: Proceedings of the NATO/ASI, Cell Biology: Molecular Dynamics of Biomembranes (Op den Kamp, J.A.F., ed.), Springer-Verlag, Berlin, pp. 137-155.

B2. Lill, R., Mayer, A., Steiner, H., Kispal, G. & Neupert, W. (1996). Molecular mechanisms of protein translocation into and across the mitochondrial outer membrane. In: Advances in Molecular and Cell Biology, Volume 17: Protein targeting to mitochondria (Bittar, F.E. & Hartl, F.U., eds.), JAI Press, Greenwich, pp. 51-70.

B3. Röhrig, S., Brockhaus, M., Steiner, H., Capell, A., Grünberg, J., Walter, J., Leimer, U., Loetscher, H., Wittenburg, N., Jacobsen, H., Baumeister, R. & Haass, C. (1999). Role of presenilin processing and caspases for amyloid beta-peptide generation and Notch signaling. In: Alzheimer’s Disease and Related Disorders (Iqbal, K., Swaab, D.F., Winblad, B. & Wisniewski, H.M., eds.), John Wiley & Sons Ltd., pp. 353-362.

B4. Steiner, H. & Haass, C. (2001). A novel protease active site motif conserved in presenilins and polytopic bacterial aspartyl proteases? In: Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics (Iqbal, K., Sisodia, S.S. & Winblad, B., eds.), John Wiley & Sons, Ltd, pp. 549-558.

B5. Steiner, H., Sastre, M., Multhaup, G., Teplow, D.B. & Haass, C. (2002) A presenilin-dependent S3-like gamma-secretase cleavage of the beta-amyloid precursor protein. In: Research and Perspectives in Alzheimer´s Disease. Notch from Neurodevelopment to Neurodegeneration: Keeping the Fate (Israel, A., De Strooper, B., Checler, F. & Christen, Y., eds.), Springer-Verlag, Berlin, pp. 59-61.

B6. Steiner, H., Sastre, M., Multhaup, G., Teplow, D.B. & Haass, C. (2002) Presenilin dependent beta-secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. In: Advances in Behavioral Biology, Volume 51: Mapping the progress of Alzheimer´s and Parkinson´s Disease (Mizuno, Y., Fisher, A. & Hanin, I., eds.), Kluwer Academic / Plenum Publishers, New York, pp. 91-94.

B7. Steiner, H., Edbauer, D., Winkler, E. & Haass, C. (2003). Functional characterization of the gamma-secretase complex. In: Alzheimer's Disease and Related Disorders: Research Advances (Iqbal, K. & Winblad, B., eds.), “Ana Aslan” International Academy of Aging, pp. 377-383.

B8. Steiner, H. & Haass, C. (2007). GxGD-type intramembrane proteases: A family of novel aspartate proteases. In: Proteases in Biology and Disease, volume 6: Intramembrane-cleaving proteases (I-CliPs) (Hooper, N.M. & Lendeckel, U., eds.), Springer-Verlag, pp. 31-49.

 

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