beta-secretase 2 (BACE2)
Homo sapiens (human)
Alzheimer's disease (AD) is a neuromuscular degenerative disease. It starts with a memory disorder, a cognitive deficiency, and Dementia advances gradually. There are senile plaque structures constituted by Aβ-amyloid in the Alzheimer patient's brain. And it is thought that this Aβ-amyloid is a causative agent of AD. Aβ-amyloid is cut down and produced from APP(amyloid precursor protein) which is membrane spanning protein by two kind of enzymes. Firstly, APP is cleaved into two fragments by β-secretase (BACE1) at the N-terminus side in the outside of a cell. Next, the C-terminal fragment of APP is cut by γ-secretase(presenilin) in the cell membrane, and Aβ-amyloid of 39-40 amino acids separates from cell. Separated Aβ-amyloid make a mistake in folding and it gathers and becomes insoluble fiber like substance. Although Aβ-amyloid is cut in normal people, it is generated excessively Alzheimer’s disease patients due to the increased β-secretase and γ-secretase activities. Thus, as a curative medicine of Alzheimer's disease, inhibitors of β-secretase and γ-secretase have been studied actively. However, it turned out that γ-secretase has an activity useful for an organism besides the processing of the APP. This means that there is potential danger of side-effects in using γ-secretase inhibitors, and its development is faced with difficulties. On the other hand, no activities other than the processing of APP have been found for β-secretase to date, so that its inhibitors are expected to be more useful curative medicines for Alzheimer's disease. β-secretase has been identified as aspartic protease type protein BACE1. Besides, there exists a homolog of BACE1, named BACE2. BACE2 was discovered in the whole body in contrast to BACE1 being specifically discovered in a brain. The physiological function of BACE2 is not known well. But it was reported BACE2 have β-secretase activity like BACE1. Furthermore, Sun et al. reported that BACE2 cleaves APP at a site different from the BACE1 cleavage site, and it may prevent production of Aβ-amyloid. Hence BACE2 is expected as another curative medicine of Alzheimer's disease.
The structure of BACE2 consists of three domains. (Fig.1). C-terminal domain, N-terminal domain, and interdomain which consists of six-stranded anti-parallel β-sheet and connects N-terminus domain and C-terminus domain. The active site of BACE2 exists in the cleft between N-terminal domain and C-terminal domain. (Fig.2). Two Aspartic acid(Asp48, Asp241) are directed toward the active site from each domain, and these are essential for activity. The beta loop called flap, it is shield like, is exists in front of substrate binding site. This flap is flexible and variable and has important role in binding substrate. The above conformational feature is common to BACE1 or other aspartic protease type proteins (Pepsin A, Cathepsin D). On the other hand, some features that distinguish BACE1/BACE2 from the general aspartic protease type protein do exist. There are two main differences. First, C-terminus is extended. It is thought that this is required for connection to the cell surface. Next, the flap is shorter by several residues compared with Pepsin A and Cathepsin D. This feature may be useful for modeling of the specific inhibitor for BACE. Compared with BACE2, BACE1 has almost the same conformation, but a delicate difference exists. The position of three loops near the active site is different, and amino acid residues contributing to the flexibility of flap are different. Pro70 exists near the turn of the flap of BACE1, whereas Lys86 exists at the same position of BACE2. These differences may influence the difference in the activities of BACE1 and BACE2.
Protein Data Bank (PDB)
author: Jun-ichi Ito