Structure of the Protease Domain of Memapsin 2 (β-Secretase) Complexed with Inhibitor

Lin, Hong; Koelsch, Gerald; Lin, Xinli; Wu, Shili; Terzyan, Simon; Ghosh, Arun K.; Zhang, Xuenjun C.; Tang, Jordan

doi:10.1126/science.290.5489.150

Cited by 692 publications

(716 citation statements)

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“…Up to now, studies of BACE have concentrated on its structure [4,45], trafficking [11,16,[46][47][48][49][50], and specific inhibition [10], but how its activity is regulated remains largely unclear. In this study, we demonstrated that BACE activity both in vitro and in vivo could be efficiently regulated by RTKs, and the regulation of BACE activity led to alterations of subsequent Aβ production.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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Amyloid-β (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by β-secretase-and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, β -site APP cleavage enzyme (BACE), has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nerve growth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

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Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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“…for 15 days) accompanied by AChE activity restoration and cognitive improvement in the Morris Water Maze test has been observed in the STZ-icv treated mice (Sharma et al 2008). This effect has been associated with the findings that HIV protease has structural homology to beta-secretase 1 (BACE) (Hong et al 2000) and thus can modulate BACE activity, and consequently, possibly, the amount of amyloid-β formation (Nunan and Small 2000). Although a quite a number of trials has been conducted with Ginkgo biloba in demented patients, a…”

Section: Nosmentioning

confidence: 99%

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

et al. 2012

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“…Although many different names were originally used to describe this activity, such as memapsin, aspartyl protease 2, or BACE1 (b-site APP cleaving enzyme-1), BACE1 is now the generally accepted term for the enzyme harboring b-secretase activity. BACE1 is a membrane-bound aspartyl protease with its active site in the lumen/extracellular space and with structural similarities to the pepsin family (Hong et al 2000). Besides BACE1, a homologous protease called BACE2 was identified (Vassar 2004).…”

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confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

911

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Structure of the Protease Domain of Memapsin 2 (β-Secretase) Complexed with Inhibitor

Cited by 692 publications

References 31 publications

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

Trafficking and Proteolytic Processing of APP

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