Abstract
BackgroundPresenilin-dependent γ-secretase cleavage of several transmembrane proteins, including amyloid-β precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling. Considering γ-secretase inhibitors as therapeutics for Alzheimer's disease, understanding the physiologically and biologically important substrate for γ-secretase activity in brains is emerging issue. To elucidate the molecular mechanism and physiological role of γ-secretase, we screened candidate molecules for γ-secretase substrates.ResultsWe show that ephrin-B1, that participates in cell-cell repulsive and attractive signaling together with its Eph receptor, constitutively undergoes ectodomain shedding and that the residual membrane-tethered fragment is sequentially cleaved by γ-secretase to release the intracellular domain. Furthermore, overexpression of membrane-tethered ephrin-B1 caused protrusion of numerous cellular processes consisted of F-actin, that required the preservation of the most C-terminal region of ephrin-B1. In contrast, soluble intracellular domain translocated into the nucleus and had no effect on cell morphology.ConclusionOur findings suggest that ephrin-B is a genuine substrate for γ-secretase and regulates the cytoskeletal dynamics through intramembrane proteolysis.
Highlights
Presenilin-dependent γ-secretase cleavage of several transmembrane proteins, including amyloid-β precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling
amyloid β peptides (Aβ) is produced by sequential proteolytic cleavages of the amyloid-β precursor protein (APP) by a set of membrane-bound proteases termed β- and γ-secretases. γ-Secretase is an unusual aspartic protease that cleaves APP within the transmembrane domain (TMD) [1]
Proteolytic processing of ephrin-B several transmembrane proteins are reported as a substrate for PS/γ-secretase-dependent intramembrane cleavage, a low homology of the amino acid sequences of transmembrane domain (TMD) has been found among these substrates [5]
Summary
Presenilin-dependent γ-secretase cleavage of several transmembrane proteins, including amyloid-β precursor protein and Notch, mediates the intramembrane proteolysis to liberate their intracellular domains that are involved in cellular signaling. Considering γ-secretase inhibitors as therapeutics for Alzheimer's disease, understanding the physiologically and biologically important substrate for γ-secretase activity in brains is emerging issue. Aβ is produced by sequential proteolytic cleavages of the amyloid-β precursor protein (APP) by a set of membrane-bound proteases termed β- and γ-secretases. Γ-Secretase is an unusual aspartic protease that cleaves APP within the transmembrane domain (TMD) [1]. Presenilins (PS) are highly conserved polytopic transmembrane proteins that are mutated in a majority of pedigrees of early-onset familial Alzheimer's disease. FAD-linked mutations in PS genes cause an increase in the production of Aβ ending at position 42, that most readily form amyloid deposits in AD brains, implicating the seminal role of γ-secretase/PS complex in the pathogenesis of AD.
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