This Article Full Text Full Text (PDF) Other Versions of this Article: MCB.02185-07v1 28/11/3663    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Google Scholar Articles by Shimizu, H. Articles by Nukina, N. PubMed PubMed Citation Articles by Shimizu, H. Articles by Nukina, N.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, June 2008, p. 3663-3671, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.02185-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production

Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan,¹ SPring-8 Center, RIKEN Harima Institute, Koto 1-1-1, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan²

Received 11 December 2007/ Returned for modification 28 January 2008/ Accepted 17 March 2008

BACE1 (β-secretase) is a transmembrane aspartic protease that cleaves the β-amyloid precursor protein and generates the amyloid β peptide (Aβ). BACE1 cycles between the cell surface and the endosomal system many times and becomes activated interconvertibly during its cellular trafficking, leading to the production of Aβ. Here we report the crystal structure of the catalytically active form of BACE1. The active form has novel structural features involving the conformation of the flap and subsites that promote substrate binding. The functionally essential residues and water molecules are well defined and play a key role in the iterative activation of BACE1. We further describe the crystal structure of the dehydrated form of BACE1, showing that BACE1 activity is dependent on the dynamics of a catalytically required Asp-bound water molecule, which directly affects its catalytic properties. These findings provide insight into a novel regulation of BACE1 activity and elucidate how BACE1 modulates its activity during cellular trafficking.

Published ahead of print on 31 March 2008.

This article has been cited by other articles:

• Vanoni, O., Paganetti, P., Molinari, M. (2008). Consequences of Individual N-glycan Deletions and of Proteasomal Inhibition on Secretion of Active BACE. Mol. Biol. Cell 19: 4086-4098 [Abstract] [Full Text]