The beta-site APP cleaving enzyme-1 (BACE1), also known as Aspartyl protease 2 and memapsin-2, mediates one of the two proteolytic cleavages of beta-amyloid precursor protein (APP) to yield the amyloid β-peptide (Abeta), a key pathogenic agent in Alzheimer's disease (AD) []. Axonal and Schwann cell BACE1 is also required for remyelination of injured nerves []. BACE1 inhibitor drugs have been evaluated for AD treatment []. BACE1 is () and MEROPS identifier A01.004.
One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) []. Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) []. This process is performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.Several independent studies identified a novel TM aspartic protease as the major beta-secretase [, , ]. This protein, termed memapsin 2 or beta-site APP cleaving enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases []. Both enzymes share significant sequence similarity with other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site. However, by contrast with other aspartyl proteases, BACE1 and BACE2 are type I TM proteins. Each protein comprises a large lumenal domain containing the active centre, a single TM domain and a small cytoplasmic tail.BACE2, also termed Asp1 and memapsin 1, was initially identified though Expressed Sequence Tag (EST) database searching. In vitro enzymaticassays with peptide substrates have demonstrated that BACE2 cleaves beta-secretase substrates in a similar fashion to BACE1 []. The BACE2 mRNA is expressed in the central nervous system and many peripheral tissues, although its expression level in neurons is substantially lower than that of BACE1 [].
Prostate apoptosis response 4 (Par-4) induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway []. It modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. It down-regulates the anti-apoptotic protein BCL2 via its interaction with WT1 []. Par-4 also regulates the amyloid precursor protein (APP) cleavage activity of BACE1 [].
One of the major neuropathological hallmarks of Alzheimer's disease (AD)is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) [].Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) []. This processis performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.Several independent studies identified a novel TM aspartic protease as themajor beta-secretase [, , ]. This protein, termed beta-site APP cleavingenzyme 1 (BACE1), shares 64% amino acid sequence similarity with a secondenzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases []. Both enzymes share significant sequence similaritywith other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site.However, by contrast with other aspartyl proteases, BACE1 and BACE2 aretype I TM proteins. Each protein comprises a large lumenal domain containingthe active centre, a single TM domain and a small cytoplasmic tail.
