The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

Dislich, Bastian; Lichtenthaler, Stefan F.

doi:10.3389/fphys.2012.00008

Cited by 74 publications

(54 citation statements)

References 229 publications

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“…In the AD brain, the BACE1 protein, not its mRNA levels, have been shown to be up-regulated (20,21). Several proteins, such as translation initiation factor eIF2␣ (22,23), Golgi-localized ␥-ear-containing ADP-ribosylation factor binding (GGA), the reticulon/Nogo family of proteins, Arf6, and sortilins, are implicated in the stability and intracellular localization of BACE1 (24 -27), but the mechanism, as well as their putative coordinated actions, remains unclear. Efforts are underway to develop drugs that would block BACE1 to prevent the generation of A␤ and alleviate the associated cognitive symptoms in AD (28,29).…”

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confidence: 99%

Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Shahani

Pryor

Swarnkar

et al. 2014

Journal of Biological Chemistry

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Background: BACE1 (␤-secretase) is an important enzyme in Alzheimer disease pathology, but how it is regulated remains unclear. Results: Rheb GTPase binds and regulates BACE1 levels and its activity, in an mTOR independent manner. Conclusion: Rheb GTPase is a novel physiological regulator of BACE1 pathway. Significance: This study establishes a novel molecular link between Rheb and BACE1 that may have a role in age-related biology and disease.

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confidence: 99%

Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Shahani

Pryor

Swarnkar

et al. 2014

Journal of Biological Chemistry

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“…Distinct sheddases may participate in intercalating processes, with disparate physiological consequences: ADAM-9, -10 (α-secretases), and -17 contribute to the nonamyloidogenic pathway of human amyloid precursor protein (APP) processing, whereas BACE-1 (β-secretase) participates in the amyloidogenic pathway. Whereas the former generates innocuous peptides, the latter gives rise to the toxic β-amyloid peptides believed to be responsible for Alzheimer's disease (11). In several instances, shedding at the membrane surface is followed by a "regulated intramembrane proteolysis" step within the membrane (1).…”

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confidence: 99%

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Arolas

Broder²,

Jefferson³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace. P hysiological processes in the extracellular milieu and the circulation require finely tuned concentrations of signal molecules such as cytokines, growth factors, receptors, adhesion molecules, and peptidases. Many of these proteins are synthesized as type-I membrane protein variants or precursors consisting of a glycosylated N-terminal ectoprotein, a transmembrane helix, and a Cterminal cytosolic tail. Their localization at the cell surface restricts their field of action to autocrine or juxtacrine processes. However, to act at a distance in paracrine, synaptic, or endocrine events, they have to be released from the plasma membrane into the extracellular space as soluble factors through "protein ectodomain shedding" (1, 2). This entails limited proteolysis and is a major posttranslational regulation mechanism that affects 2-4% of the proteins on the cell surface, occurs at or near the plasma membrane (3), and apparently follows a common release mechanism (2). It may also proteolytically inactivate proteins to terminate their function on the cell surface (4). Peptidases engaged in such processing are "sheddases" and the most studied transmembrane sheddases are members of the adamalysin/ADAMs (4, 5) and matrix-metalloproteinase (MMP) (6) families within the metzincin clan of metallopeptidases (MPs) (7-9). These include ADAM

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“…Plasma membrane acts as a selective barrier as well as means of communication with extracellular environment through signal transduction in a cell (Harder, 2012; Astro and de Curtis, 2015). In addition, membranes compartmentalize eukaryotic cell into different subcellular structures and act as scaffold for certain enzymatic reactions that allow reactions to be spatially confined inside a cell and 3-D cytosol to 2D membrane (Dislich and Lichtenthaler, 2012), respectively.…”

Section: Introductionmentioning

confidence: 99%

Budding Yeast: An Ideal Backdrop for In vivo Lipid Biochemistry

Singh

2017

Front. Cell Dev. Biol.

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Biological membranes are non-covalent assembly of lipids and proteins. Lipids play critical role in determining membrane physical properties and regulate the function of membrane associated proteins. Budding yeast Saccharomyces cerevisiae offers an exceptional advantage to understand the lipid-protein interactions since lipid metabolism and homeostasis are relatively simple and well characterized as compared to other eukaryotes. In addition, a vast array of genetic and cell biological tools are available to determine and understand the role of a particular lipid in various lipid metabolic disorders. Budding yeast has been instrumental in delineating mechanisms related to lipid metabolism, trafficking and their localization in different subcellular compartments at various cell cycle stages. Further, availability of tools and enormous potential for the development of useful reagents and novel technologies to localize a particular lipid in different subcellular compartments in yeast makes it a formidable system to carry out lipid biology. Taken together, yeast provides an outstanding backdrop to characterize lipid metabolic changes under various physiological conditions.

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The Membrane-Bound Aspartyl Protease BACE1: Molecular and Functional Properties in Alzheimer’s Disease and Beyond

Cited by 74 publications

References 229 publications

Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Budding Yeast: An Ideal Backdrop for In vivo Lipid Biochemistry

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