Dual Mechanisms for Shedding of the Cellular Prion Protein

Parkin, Edward T.; Watt, Nicole T.; Turner, Anthony J.; Hooper, Nigel M.

doi:10.1074/jbc.m312105200

Cited by 125 publications

(107 citation statements)

References 48 publications

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“…PrP C may be cleaved at its GPI-anchor, allowing shedding of PrP C species from a cell by both protease and phospholipase mediated mechanisms [26][27][28]. PrP C is also subject to two well-described internal cleavage events known as a-and b-cleavage [29].…”

Section: Introductionmentioning

confidence: 99%

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Lewis

Johanssen

Crouch

et al. 2015

Cell. Mol. Life Sci.

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The cellular prion protein (PrP C ) is a ubiquitously expressed protein of currently unresolved but potentially diverse function. Of putative relevance to normal biological activity, PrP C is recognized to undergo both a-and b-endoproteolysis, producing the cleavage fragment pairs N1/C1 and N2/C2, respectively. Experimental evidence suggests the likelihood that these processing events serve differing cellular needs. Through the engineering of a C-terminal c-myc tag onto murine PrP C , as well as the selective use of a far-Cterminal anti-PrP antibody, we have identified a new PrP C fragment, nominally 'C3', and elaborating existing nomenclature, 'c-cleavage' as the responsible proteolysis. Our studies indicate that this novel c-cleavage event can occur during transit through the secretory pathway after exiting the endoplasmic reticulum, and after PrP C has reached the cell surface, by a matrix metalloprotease.We found that C3 is GPI-anchored like other C-terminal and full length PrP C species, though it does not localize primarily at the cell surface, and is preferentially cleaved from an unglycosylated substrate. Importantly, we observed that C3 exists in diverse cell types as well as mouse and human brain tissue, and of possible pathogenic significance, c-cleavage may increase in human prion diseases. Given the likely relevance of PrP C processing to both its normal function, and susceptibility to prion disease, the potential importance of this previously underappreciated and overlooked cleavage event warrants further consideration.

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Section: Introductionmentioning

confidence: 99%

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Lewis

Johanssen

Crouch

et al. 2015

Cell. Mol. Life Sci.

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“…In addition, like APP, PrP C is shed from the cell surface by zinc metalloproteases and is subject to endoproteolysis by ADAM10 and ADAM17 (12)(13)(14)(15). As a result of these pathological, genetic, and mechanistic similarities, we were led to investigate whether PrP C alters the proteolytic processing of APP.…”

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Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Parkin

Watt²,

Hussain³

et al. 2007

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

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Proteolytic processing of the amyloid precursor protein (APP) by ␤-secretase, ␤-site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid ␤ (A␤) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrP C ), the causative agent of the transmissible spongiform encephalopathies such as CreutzfeldtJakob disease in humans, remains enigmatic. Because both APP and PrP C are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrP C in the proteolytic processing of APP. Cellular overexpression of PrP C inhibited the ␤-secretase cleavage of APP and reduced A␤ formation. Conversely, depletion of PrP C in mouse N2a cells by siRNA led to an increase in A␤ peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapieinfected mice, A␤ levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the ␤-secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrP C on the ␤-secretase cleavage of APP required the localization of PrP C to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrP C via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A␤ is regulated by PrP C and may have implications for both Alzheimer's and prion diseases.lipid raft ͉ proteolysis ͉ scrapie ͉ glycosaminoglycan A lzheimer's disease (AD) is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles within the afflicted brain. The major constituents of senile plaques are the amyloid ␤ (A␤) peptides, which are derived from the proteolytic processing of the amyloid precursor protein (APP) (1). In the amyloidogenic pathway, ␤-secretase cleavage of APP yields a soluble N-terminal fragment sAPP␤, along with a short membrane-bound C-terminal fragment that is subsequently cleaved by ␥-secretase to release the A␤ peptides. In the alternative, nonamyloidogenic pathway, ␣-secretase cleaves APP within the A␤ sequence, thus precluding the formation of A␤, and releases a soluble N-terminal fragment sAPP␣. The transmembrane aspartyl protease, ␤-site APP cleaving enzyme (BACE1), has been identified as ␤-secretase (2), members of the ADAM (a disintegrin and metalloprotease) family, particularly ADAM10 and ADAM17, are responsible for ␣-secretase cleavage (3), while a complex of at least four proteins, the presenilins, nicastrin, Aph-1, and Pen-2, constitutes the ␥-secretase (2).The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs) that include CreutzfeldtJakob disease (CJD), Gerstmann-Scheinker-Straussler (GSS) disease, kuru and fatal familial insomnia in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep (4). In these diseases, the normal ce...

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“…In addition, PrP C can be cleaved near its C terminus or within the GPI anchor and be secreted or "shed" into the extracellular milieu (16,17). As for the cell-associated trafficking of PrP C , the significance of shedding is poorly understood, but it clearly liberates PrP C to potentially participate in membrane associations not readily available to it while tethered through a GPI anchor at its C terminus.…”

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confidence: 99%

Anionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain

Boland

Hatty

Separovic

et al. 2010

Journal of Biological Chemistry

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Although the N terminus of the prion protein (PrP C ) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP C and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.

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Dual Mechanisms for Shedding of the Cellular Prion Protein

Cited by 125 publications

References 48 publications

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Prion protein “gamma-cleavage”: characterizing a novel endoproteolytic processing event

Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein

Anionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain

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