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Beta-site APP-cleaving enzyme 2 (BACE2, also called Memapsin 1), is a 49 kDa type 1 membrane-bound aspartyl protease homologue of BACE1. In vitro, BACE2 performs function in keeping with BACE1, cleaving APP at the β-secretase cleavage site.
BACE2 Disable Function Results in Hyperactive Insulin/PI3K/mTOR Signaling
The melanosome pattern in vertebrates is essential for mate selection and protection from UV damage. Patterns can be influenced by long-term factors in circulation, like hormones. However, it is not known how their activity is controlled in recipient cells to prevent excessive cell number and migration. The zebrafish wanderlust mutant has a mutation in the shedding enzyme BACE2 and exhibits hyperdendritic and hyperproliferative melanocytes that are localized to the site of abnormality. Recent study has screen out some chemical to suppress the wanderlust phenotype and find that inhibition of insulin/PI3Kγ/mTOR signaling rescues the defect. In normal physiological processes, BACE2 can lyse insulin receptors. Similarly, the BACE2 loss function results in hyperactive insulin /PI3K/mTOR signaling. Insulin B, an isoform of insulin, which is enriched in the head, drives the melanophore defect. These results suggest that insulin signaling is negatively regulated by melanophore-specific expression of shedding enzymes, highlighting how long-distance factors can be regulated in a cell-type-specific manner.
Fig 1. BACE2 mutation causes defects in melanocyte patterning and morphology (Zhang et al. Developmental Cell. 2018).
Human Islet Amyloid Polypeptide as a BACE2 Substrate
Islet amyloid polypeptide (IAPP) forms islet amyloid, which is a hallmark pathological feature of type 2 diabetes. The IAPP is stored in the secretory granules of beta cells of the pancreas, and maintains glucose homeostasis along with insulin. Under normal physiological conditions, IAPP is innocuous. However, during the production or processing of IAPP, the imbalance may result in homodimer, leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets.
Studies have indicated that BACE2 mainly functions by cleaving Aβ at phenylalanines 19 and 20, referred to as the “theta” secretase site, thus resulting in fragmented peptides that cannot dimerize. Recently, the researchers extended the description of BACE2 to that of an avid Aβ-degrading protease, supporting BACE2 as a therapeutic candidate for AD. In humans, BACE2 is expressed at low levels in the central nervous system but at higher levels in peripheral organs including the stomach, colon, arteries and pancreatic beta-cells. The recent studies have established that hIAPP (human IAPP) is a substrate for BACE2 and proteolysis produced by this interaction can significantly modulate hIAPP fibril formation. BACE2 cleave hIAPP at the phenylalanine residues at positions 15 and 23. BACE1 can also cleave hIAPP, but only at the position F15, additional cleavage at position F23 by BACE2 appears to modulate hIAPP fibril formation to an even greater extent. The phenotypes associated with hIAPP-mediated amyloidosis is extensive and the findings suggest a multidimensional purpose for the targeting of hIAPP.
BACE2 Cleave PotassiumChannel Kv2.1 Result in Reduction of Neuronal Apoptosis
Potassium channel Kv2.1 regulates potassium currents in cortical neurons, and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. A recent study identified that Kv2.1 is a novel substrate of BACE2 with three cleavage sites at Thr376, Ala717, and Ser769. Electrophysiological recordings showed that cleavage of Kv2.1 by BACE2 caused loss-of-function of this potassium channel. Furthermore, three cleaved Kv2.1 formed Kv2.1-1-375, Kv2.1-1-716, which significantly reduced neuronal apoptosis. Therefore, cleavage of Kv2.1 by BACE2 has a protective effect on neurons.