QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, November 15, 2006, 26(46):12081-12088; doi:10.1523/JNEUROSCI.3614-06.2006

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (36) Citing Articles via Google Scholar Google Scholar Articles by Sato, C. Articles by Iwatsubo, T. Search for Related Content PubMed PubMed Citation Articles by Sato, C. Articles by Iwatsubo, T.

 Previous Article  |  Next Article 

Neurobiology of Disease
Structure of the Catalytic Pore of -Secretase Probed by the Accessibility of Substituted Cysteines

Chihiro Sato, Yuichi Morohashi, Taisuke Tomita, and Takeshi Iwatsubo

Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

Correspondence should be addressed to either of the following: Taisuke Tomita or Takeshi Iwatsubo, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: taisuke{at}mol.f.u-tokyo.ac.jp or Email: iwatsubo{at}mol.f.u-tokyo.ac.jp

Several single-span membrane proteins are cleaved within their transmembrane domains (TMDs) by intramembrane-cleaving proteases, although the structure of the active site executing intramembrane cleavage remains unknown. Here we use the substituted cysteine accessibility method to examine the structure of presenilin-1, a catalytic subunit of -secretase, involved in amyloid protein generation in Alzheimer's disease and Notch signaling. We show that TMD6 and TMD7 of presenilin-1 contribute to the formation of a hydrophilic pore within the membrane. Residues at the luminal portion of TMD6 are predicted to form a subsite for substrate or inhibitor binding on the -helix facing a hydrophilic milieu, whereas those around the GxGD catalytic motif within TMD7 are highly water accessible, suggesting formation of a hydrophilic structure within the pore. Collectively, our data suggest that the active site of -secretase resides in a catalytic pore filled with water within the lipid bilayer and is tapered around the catalytic aspartates.

Key words: Alzheimer's disease; intramembrane-cleaving protease; presenilin; substituted cysteine accessibility method; A peptide; proteolysis; structure

---

Received Aug. 20, 2006; revised Oct. 9, 2006; accepted Oct. 11, 2006.

Correspondence should be addressed to either of the following: Taisuke Tomita or Takeshi Iwatsubo, Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Email: taisuke{at}mol.f.u-tokyo.ac.jp or Email: iwatsubo{at}mol.f.u-tokyo.ac.jp

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2006 26: i. [Full Text]  

This article has been cited by other articles:

				I. Hayashi, S. Takatori, Y. Urano, H. Iwanari, N. Isoo, S. Osawa, M. A. Fukuda, T. Kodama, T. Hamakubo, T. Li, et al. Single Chain Variable Fragment against Nicastrin Inhibits the {gamma}-Secretase Activity J. Biol. Chem., October 9, 2009; 284(41): 27838 - 27847. [Abstract] [Full Text] [PDF]

				R. Pardossi-Piquard, S.-P. Yang, S. Kanemoto, Y. Gu, F. Chen, C. Bohm, J. Sevalle, T. Li, P. C. Wong, F. Checler, et al. APH1 Polar Transmembrane Residues Regulate the Assembly and Activity of Presenilin Complexes J. Biol. Chem., June 12, 2009; 284(24): 16298 - 16307. [Abstract] [Full Text] [PDF]

				M. S. Wolfe Intramembrane-cleaving Proteases J. Biol. Chem., May 22, 2009; 284(21): 13969 - 13973. [Full Text] [PDF]

				E. Futai, S. Yagishita, and S. Ishiura Nicastrin Is Dispensable for {gamma}-Secretase Protease Activity in the Presence of Specific Presenilin Mutations J. Biol. Chem., May 8, 2009; 284(19): 13013 - 13022. [Abstract] [Full Text] [PDF]

				L. Martin, R. Fluhrer, and C. Haass Substrate Requirements for SPPL2b-dependent Regulated Intramembrane Proteolysis J. Biol. Chem., February 27, 2009; 284(9): 5662 - 5670. [Abstract] [Full Text] [PDF]

				L. Placanica, L. Tarassishin, G. Yang, E. Peethumnongsin, S.-H. Kim, H. Zheng, S. S. Sisodia, and Y.-M. Li Pen2 and Presenilin-1 Modulate the Dynamic Equilibrium of Presenilin-1 and Presenilin-2 {gamma}-Secretase Complexes J. Biol. Chem., January 30, 2009; 284(5): 2967 - 2977. [Abstract] [Full Text] [PDF]

				H. Steiner, E. Winkler, and C. Haass 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-1 J. Biol. Chem., December 12, 2008; 283(50): 34677 - 34686. [Abstract] [Full Text] [PDF]

				H. Steiner, R. Fluhrer, and C. Haass Intramembrane Proteolysis by {gamma}-Secretase J. Biol. Chem., October 31, 2008; 283(44): 29627 - 29631. [Abstract] [Full Text] [PDF]

				A. Tolia, K. Horre, and B. De Strooper Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of {gamma}-Secretase J. Biol. Chem., July 11, 2008; 283(28): 19793 - 19803. [Abstract] [Full Text] [PDF]

				C. Sato, S. Takagi, T. Tomita, and T. Iwatsubo The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the {gamma}-Secretase J. Neurosci., June 11, 2008; 28(24): 6264 - 6271. [Abstract] [Full Text] [PDF]

				K. Koide, K. Ito, and Y. Akiyama Substrate Recognition and Binding by RseP, an Escherichia coli Intramembrane Protease J. Biol. Chem., April 11, 2008; 283(15): 9562 - 9570. [Abstract] [Full Text] [PDF]

				D. Spasic and W. Annaert Building {gamma}-secretase - the bits and pieces J. Cell Sci., February 15, 2008; 121(4): 413 - 420. [Abstract] [Full Text] [PDF]

				B. Zhao, M. Yu, M. Neitzel, J. Marugg, J. Jagodzinski, M. Lee, K. Hu, D. Schenk, T. Yednock, and G. Basi Identification of {gamma}-Secretase Inhibitor Potency Determinants on Presenilin J. Biol. Chem., February 1, 2008; 283(5): 2927 - 2938. [Abstract] [Full Text] [PDF]

				S. Yagishita, M. Morishima-Kawashima, S. Ishiura, and Y. Ihara A 46 Is Processed to A 40 and A 43, but Not to A 42, in the Low Density Membrane Domains J. Biol. Chem., January 11, 2008; 283(2): 733 - 738. [Abstract] [Full Text] [PDF]

				R. L. Lieberman and M. S. Wolfe From rhomboid function to structure and back again PNAS, May 15, 2007; 104(20): 8199 - 8200. [Full Text] [PDF]

				N. Isoo, C. Sato, H. Miyashita, M. Shinohara, N. Takasugi, Y. Morohashi, S. Tsuji, T. Tomita, and T. Iwatsubo Abeta42 Overproduction Associated with Structural Changes in the Catalytic Pore of {gamma}-Secretase: COMMON EFFECTS OF PEN-2 N-TERMINAL ELONGATION AND FENOFIBRATE J. Biol. Chem., April 27, 2007; 282(17): 12388 - 12396. [Abstract] [Full Text] [PDF]

				K. Koide, S. Maegawa, K. Ito, and Y. Akiyama Environment of the Active Site Region of RseP, an Escherichia coli Regulated Intramembrane Proteolysis Protease, Assessed by Site-directed Cysteine Alkylation J. Biol. Chem., February 16, 2007; 282(7): 4553 - 4560. [Abstract] [Full Text] [PDF]

				R. L. Lieberman and M. S. Wolfe Membrane-embedded protease poses for photoshoot PNAS, January 9, 2007; 104(2): 401 - 402. [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help