BACE1

Official Full Name

beta-secretase 1

Organism

Homo sapiens

Gene ID

23621

Background

This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

Synonyms

ASP2; BACE; HSPC104

Bio Chemical Class

Peptidase

Protein Sequence

MAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSFVEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGILGLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRITILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSACHVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQWRCLRCLRQQHDDFADDISLLK

Open

Disease

Alzheimer disease

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

Cat.No.	Product Name	Price
CSC-DC001291	Panoply™ Human BACE1 Knockdown Stable Cell Line	Inquiry
CSC-SC001291	Panoply™ Human BACE1 Over-expressing Stable Cell Line	Inquiry
CLOE-1764	Human BACE1(Fc) HEK293 Cell Lysate	Inquiry
CLOE-1765	Human BACE1(His) HEK293 Cell Lysate	Inquiry
CLOE-1766	Human BACE1 HEK293 Cell Lysate	Inquiry
CLOE-3000	Mouse Bace1 (His) HEK293 Cell Lysate	Inquiry

Cat.No.	Product Name	Price
AD01681Z	Human BACE1 adenoviral particles	Inquiry
LV06007L	human BACE1 (NM_001207048) lentivirus particles	Inquiry
LV06008L	human BACE1 (NM_138972) lentivirus particles	Inquiry
LV06009L	human BACE1 (NM_001207049) lentivirus particles	Inquiry
LV06010L	human BACE1 (NM_138971) lentivirus particles	Inquiry
LV06011L	human BACE1 (NM_138973) lentivirus particles	Inquiry
LV06012L	human BACE1 (NM_012104) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH244568	shRNA set against Mouse BACE1 (NM_011792.5)	Inquiry
SHH244570	shRNA set against Rat BACE1 (NM_019204.1)	Inquiry
SHG066877	shRNA set against Rat Bace1(NM_019204.1)	Inquiry
SHH244562	shRNA set against Human BACE1 (NM_138973.3)	Inquiry
SHW017612	shRNA set against Danio rerio BACE1 (NM_205704)	Inquiry

Cat.No.	Product Name	Price
CDCB157344	Mouse BACE1 ORF clone (NM_011792.4)	Inquiry
CDFR011501	Rat Bace1 cDNA Clone(NM_019204.1)	Inquiry
MiUTR1R-00504	BACE1 miRNA 3'UTR clone	Inquiry
MiUTR3H-06677	BACE1 miRNA 3'UTR clone	Inquiry
CDCB179087	Danio rerio BACE1 ORF Clone (NM_205704)	Inquiry
CDCB191655	Rabbit BACE1 ORF clone (XM_002708373.2)	Inquiry
CDCG001458	Mouse BACE1 ORF clone(NM_011792.5)	Inquiry
CDCR032928	Mouse Bace1 ORF clone (NM_001145947.1)	Inquiry
CDCR032934	Human BACE1 ORF clone (NM_001207049.1)	Inquiry
CDCR032936	Human BACE1 ORF clone (NM_001207048.1)	Inquiry
CDCR378364	Rat Bace1 ORF Clone(NM_019204.1)	Inquiry
CDCS409707	Human BACE1 ORF Clone (BC065492)	Inquiry

Detailed Information

The production of 40 or 42 amino acids long amyloid-β peptide accumulated in the brain is the central pathological feature of Alzheimer's disease and largely consists of amyloid-β peptides. Amyloid-β is formed through sequential proteolytic processing of the amyloid precursor protein (APP), catalyzed by the β- and γ-secretases. The aspartyl protease β-site APP cleaving enzyme 1 (BACE1) cleaves APP predominantly at a unique site, whereas the c-secretase complex cleaves the resulting carboxy-terminal fragment at several sites, with preference for positions 40 and 42, leading to formation of amyloid β1-40 (Aβ1-40) and Aβ1-42 peptides.

Extracellular cleavage of APP by BACE1 produces soluble extracellular fragments and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since γ-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by α-secretase instead of BACE1 prevents the final production of amyloid-β. Unlike APP and the presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE1 lead to early-onset, familial Alzheimer's disease, which is a rare form of the disorder. Nevertheless, it has been shown that this level of enzyme is elevated in the more common late-onset sporadic Alzheimer's disease. The physiological purpose of BACE cleavage of APP and other transmembrane proteins is unclear. BACE2 is a close homolog of BACE1 and there is no reported APP cleavage in vivo. However, single residue mutations in APP reduce the ability of BACE1 to cleave it to produce amyloid-beta and reduce the risk of Alzheimers and other cognitive declines. Thorlakur et al. has shown that a coding mutation (A673T) in the APP gene that protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The A673T substitution is located at position 2 in the amyloid-β peptide.

Fig 1. Processing of the amyloid precursor protein.

Wanxia et al. has identificated reticulon family members as binding partners of BACE1. RTN3 and RTN4B are members of the reticulon family, all of which contain a highly conserved reticulon homology domain (RHD) of about 188 amino acids with two putative transmembrane regions separated by a 66-residue loop. They found that two membrane-associated proteins, RTN3 and RTN4B, are both present in BACE1 immunocomplexes. The reticulon family of cellular proteins interacts with BACE1 and decreases both BACE1 cleavage of APP and Aβ production. RTN3 is the principal BACE1-interacting protein in human brain. It seems conceivable that small changes in reticulon expression in human brain might potentially affect long-term Aβ production and that, in turn, this could either accelerate or decelerate the deposition of amyloid in brain. Overexpression of RTN3 can inhibit Aβ production, owing to the sequestering of BACE1 away from its cellular APP substrate. Reticulon proteins share a highly conserved membrane-associated RHD, but their N-terminal regions are divergent. All tested reticulon proteins bind to BACE1 and inhibit its activity, suggesting that reticulon proteins have shared functions in addition to the specific roles mediated by their distinct N-terminal domains. The physiological meaning of the binding of reticulon proteins to BACE1 remains to be discovered. It is also unclear whether or not BACE1 binds to reticulon proteins directly. It is possible that the binding of BACE1 to reticulon proteins is in an ‘on-and-off’ state in cells because the binding of endogenous proteins is clearly weak. Increasing the expression of either RTN3 or BACE1 increased this binding and the increase in binding clearly blocked the interaction of BACE1 with its cellular APP substrate and reduced the catalytic action of BACE1.

References:

Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9.
Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE. Plasmepsin V licenses. Plasmodium proteins for export into the host erythrocyte. Nature. 2010;463(7281):632-636.
He W1, Lu Y, Qahwash I, Hu XY, Chang A, Yan R. Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation. Nat Med. 2004 Sep;10(9):959-65. Epub 2004 Aug 1.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science. 314 (5799): 664–6.

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