BACE1 Protein Overview: Sequence, Structure, Function and Protein Interaction

BACE1 Protein Overview

Cerebral deposition of amyloid beta peptide is an early and critical feature of Alzheimer disease (AD; 104300). Amyloid beta generation depends on proteolytic cleavage of amyloid precursor protein (APP; 104760) by 2 proteases, beta-secretase and gamma-secretase (see PSEN1; 104311). Vassar et al. (1999) reported the cloning of a human transmembrane aspartic protease that had all the known characteristics of the beta-secretase. Using an expression cloning strategy, they identified a clone that shared significant sequence similarity with members of the pepsin subfamily of aspartic proteases. This clone encoded a novel protein, designated BACE for 'beta-site APP-cleaving enzyme.' The BACE open reading frame encodes a protein of 501 amino acids containing a 21-amino acid signal peptide followed by a proprotein domain spanning amino acids 22 to 45. The luminal domain of the mature protein is followed by 1 predicted transmembrane domain and a short cytosolic C-terminal tail of 24 amino acids. BACE was predicted to be a type 1 transmembrane protein with the active site on the luminal side of the membrane, where beta-secretase cleaves APP. The BACE protein shares greatest amino acid identity (30%) with cathepsin E (116890). Rat and mouse BACE orthologs have 96% amino acid sequence identity with the human BACE protein. Northern blot analysis of human BACE mRNA in adult peripheral tissues and various subregions of the brain detected 3 transcripts of approximately 7.0, 4.4, and 2.6 kb. By in situ hybridization, expression of BACE mRNA in rat brain was observed at higher levels in neurons than in glia, supporting the idea that neurons are the primary source of the extracellular A-beta deposited in amyloid plaques. Vassar et al. (1999) ascribed the difference between the apparent and calculated molecular weight (approximately 70 and 51 kD, respectively) of the BACE protein to N-linked glycosylation. Immunostaining demonstrated intracellular localization of BACE to the Golgi and endosomes. Yan et al. (1999) and Hussain et al. (1999) independently cloned BACE, which they both called ASP2. Sinha et al. (1999) also independently cloned BACE, which they referred to as p501. Sinha et al. (1999) used a classic protein fractionation approach. To purify BACE, Sinha et al. (1999) designed several variants of the APP sequence spanning the beta site, including so-called transition-state analogs. This approach allowed them to pull out their candidate protease from human brain extracts, with a 300,000-fold enrichment. By RT-PCR of an adult frontal cortex cDNA library, Tanahashi and Tabira (2001) identified 3 minor BACE1 transcripts resulting from in-frame alternative splicing. These variants encode proteins with deletions of 25, 44, and 69 amino acids, designated BACE1-476, BACE1-457, and BACE1-432, respectively, compared with the full-length protein, BACE1-501. The 2 shortest isoforms lack 2 of the 4 N-glycosylation sites found in BACE1-501. RT-PCR detected expression of the minor BACE1 transcripts in several human cell lines and tissues, with highest abundance in pancreas and brain. Ehehalt et al. (2002) cloned BACE1-476, which they called BACE1B, from human hippocampus and exocrine pancreas cDNA libraries and BACE1-457, which they called BACE1C, from the pancreas cDNA library. Following overexpression in mammalian kidney cells, fluorescence-tagged BACE1-501, which Ehehalt et al. (2002) called BACE1A, was expressed predominantly in perinuclear post-Golgi membranes, and also in vesicular structures throughout the cytoplasm and on the cell surface. BACE1-476 and BACE1-457 were restricted to the endoplasmic reticulum.

BACE1 protein family

Belongs to the peptidase A1 family.

BACE1 protein name

Recommended name
Beta-secretase 1
Alternative name
Aspartyl protease 2 ASP2 Asp 2 Beta-site amyloid precursor protein cleaving enzyme 1 Beta-site APP cleaving enzyme 1 Memapsin-2 Membrane-associated aspartic protease 2

BACE1 Protein Sequence

Species Human BACE1 protein
Length 501
Mass (Da) 55764
Sequence Human BACE1 protein sequence
Species Mouse BACE1 protein
Length 501
Mass (Da) 55748
Sequence Mouse BACE1 protein sequence
Species Rat BACE1 protein
Length 501
Mass (Da) 55807
Sequence Rat BACE1 protein sequence

BACE1 Protein Molecular Weight & PI

Beta-secretase 1 precursor (EC 3.4.23.46) (Aspartyl protease 2) (ASP2) (Asp 2) (Beta-site amyloid precursor protein cleaving enzyme 1) (Beta-site APP cleaving enzyme 1) (Memapsin-2) (Membrane-associated aspartic protease 2)Homo sapiens (Human).

The parameters have been computed for the following feature

FT CHAIN 46-501 Beta-secretase 1.

Molecular weight (Da)

51031.06

Theoretical pI

4.96

BACE1 Protein Structure

New substrate binding pockets for beta-secretase.
Deposited
2004-10-04   Released:  2005-03-22
Deposition Author(s)
Turner III, R.T., Hong, L., Koelsch, G., Ghosh, A.K., Tang, J.
Organism(s)
Homo sapiens
Expression System
Escherichia coli BL21
Experimental Data Snapshot
Method
X-RAY DIFFRACTION
Resolution
1.9000 Å
R-Value Free
0.220
1XN2 From PDB

Human BACE1 protein Secondary structure

BACE1 Protein Interaction

Recombinant BACE1 Protein Feature

BACE1 Protein, Human, Recombinant (hFc Tag)

High Purity
> 90 % as determined by SDS-PAGE
Low Endotoxin
< 1.0 EU per μg of the protein as determined by the LAL method
High Activity
Measured by its ability to cleave a fluorogenic peptide substrate, Mca-SEVNLDAEFRK(Dpn)RR-NH2, (R&D Systems, Catalog # ES004). The specific activity is >0.5 pmoles/min/μg.

Recombinant BACE1 protein citations

Title
From Bace1 inhibitor to multifunctionality of tryptoline and tryptamine triazole derivatives for alzheimer's disease
Year
2012
Author
J Jiaranaikulwanitch, P Govitrapong, VV Fokin…
Journal
molecules
Title
Neuritogenic activity of bi-functional bis-tryptoline triazole
Year
2017
Author
Jiaranaikulwanitch, J;Tadtong, S;Govitrapong, P;Fokin, VV;Vajragupta, O;
Journal
Bioorg. Med. Chem
Title
Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
Year
2020
Author
Suwanttananuruk, P;Jiaranaikulwanitch, J;Waiwut, P;
Journal
researchgate.net

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