Regulation of Brain G-protein Go by Alzheimer's Disease Gene Presenilin-1

Smine, Abdelkrim; Xu, Xuemin; Nishiyama, Kazutoshi; Katada, Toshiaki; Gambetti, Pierluigi; Yadav, Satya Prakash; Wu, Xian; Shi, Yongchang; Yasuhara, Shingo; Homburger, Vincent; Okamoto, Takashi

doi:10.1074/jbc.273.26.16281

Cited by 58 publications

(30 citation statements)

References 48 publications

(54 reference statements)

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“…An antibody raised against the last ten residues of PS1, 4627 (42), detects PS1 CTF on a Western blot but is not efficient for co-immunoprecipitations under conditions that keep the ␥-secretase complex intact (43), supporting the notion that the epitope could be hidden in the complex. In addition to the other known ␥-secretase components, a number of proteins have been suggested to bind to the C terminus of PS1, including the brain G-protein G o (44), the calcium-binding protein calsenilin (45), the PS1-associated protein (46), the neuronal adaptor proteins X11␣ and X11␤ (47), and telencephalin (48). Most of these studies have identified PS1-binding proteins by using peptides corresponding to the last 39 -79 residues of the PS1 C terminus for glutathione S-transferase pull-down experiments or yeast two-hybrid screens.…”

Section: Discussionmentioning

confidence: 99%

A Nine-transmembrane Domain Topology for Presenilin 1

Laudon

Hansson

Melén

et al. 2005

Journal of Biological Chemistry

167

125

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Presenilin (PS) provides the catalytic core of the ␥-secretase complex. ␥-Secretase activity leads to generation of the amyloid ␤-peptide, a key event implicated in the pathogenesis of Alzheimer disease. PS has ten hydrophobic regions, which can all theoretically form membrane-spanning domains. Various topology models have been proposed, and the prevalent view holds that PS has an eighttransmembrane (TM) domain organization; however, the precise topology has not been unequivocally determined. Previous topological studies are based on non-functional truncated variants of PS proteins fused to reporter domains, or immunocytochemical staining. In this study, we used a more subtle N-linked glycosylation scanning approach, which allowed us to assess the topology of functional PS1 molecules. Glycosylation acceptor sequences were introduced into full-length human PS1, and the results showed that the first hydrophilic loop is oriented toward the lumen of the endoplasmic reticulum, whereas the N terminus and large hydrophilic loop are in the cytosol. Although this is in accordance with most current models, our data unexpectedly revealed that the C terminus localized to the luminal side of the endoplasmic reticulum. Additional studies on the glycosylation pattern after TM domain deletions, combined with computer-based TM protein topology predictions and biotinylation assays of different PS1 mutants, led us to conclude that PS1 has nine TM domains and that the C terminus locates to the lumen/extracellular space.Most proteases operate in aqueous environments, but ␥-secretase, along with other intramembrane cleaving proteases, is unusual in the sense that it executes proteolysis in the lipid bilayer (1). ␥-Secretase is a high molecular weight protein complex composed of presenilin (PS) 2 1 or 2, nicastrin, Aph-1, and Pen-2 (2-5). Growing evidence suggests that the polytopic PS1 protein is a TM aspartyl protease and that two of its aspartate residues, Asp-257 in hydrophobic domain (HD) 6 and Asp-385 in HD 8, form the catalytic site of the ␥-secretase complex (6 -8). An endoproteolytic cleavage within HD 7 of PS1 generates an N-terminal fragment (NTF) and a C-terminal fragment (CTF) (9). The NTF/ CTF heterodimer is believed to be the biologically active form of PS. Nicastrin, Aph-1, and Pen-2 are all essential cofactors in the ␥-secretase complex, but their precise biochemical functions are not fully known. Nicastrin and Aph-1 have been proposed to form a subcomplex that can stabilize full-length PS, and the final addition of Pen-2 has been suggested to trigger PS endoproteolysis (10) and stabilize the NTF/CTF heterodimer (11). ␥-Secretase cleavage occurs within the lipid bilayer of the membrane through a mechanism referred to as "regulated intramembrane proteolysis" (12). Recently, not only APP, but a large number of other type-1 TM proteins, such as the Notch receptors, CD44 and E-cadherin, have been shown to undergo PS-dependent regulated intramembrane proteolysis (reviewed in Ref. 13). Given that target proteins of ␥-secret...

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Section: Discussionmentioning

confidence: 99%

A Nine-transmembrane Domain Topology for Presenilin 1

Laudon

Hansson

Melén

et al. 2005

Journal of Biological Chemistry

167

125

View full text Add to dashboard Cite

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“…A role for PS as a heterotrimeric GPCR is suggested. In vitro experiments (26) suggest that within the 39-aa residue C-terminal domain of PS-1 (located in the cytoplasm in all three topographic models of PS-1, Fig. 1), there exists a specific binding and regulating domain for the brain G o protein, but the possibility that PS-1 may be a GPCR has not been elaborated upon since that report.…”

Section: Discussionmentioning

confidence: 99%

“…The PS proteins show no extensive amino acid homologies with any of the four subfamilies of GPCRs. However, the region of the C-terminal domain of PS-1 that binds G o shows significant local amino acid sequence homologies with the G-binding domains of the D2-dopaminergic and the 5HT-1B receptors, both of which are 7-TM GPCRs, as well as of the G protein-activating oligopeptide, mastoparan (26). These homologies strengthen the case that PS-1 and other PS proteins are 7-TM GPCRs, but in vivo experiments are required to establish this.…”

Section: Discussionmentioning

confidence: 99%

The presenilins turned inside out: Implications for their structures and functions

Dewji

Valdez²,

Singer³

2004

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

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The presenilin (PS) proteins are polytopic integral membrane proteins that are critically involved in the development of Alzheimer's disease. The topography of the PS molecule in the endoplasmic reticulum membrane is widely accepted as exhibiting eighthydrophobic-transmembrane (8-TM) helices. We have previously provided evidence, however, that the intact PS molecule is also present in the cell surface where it exhibits exclusively a 7-TM topography, which differs in significant structural features from the 8-TM model. This evidence, however, has been disparaged and generally rejected by researchers in Alzheimer's disease. The 7-TM model is definitively demonstrated in the present study for PS-1 at the surfaces of PS-1-transfected cells and for endogenous PS-1 at the surfaces of untransfected cells, by immunofluorescence studies using mAbs. These studies force substantial revision of current views of the structural and functional properties of the PS proteins.Alzheimer's disease ͉ protein topology ͉ seven-transmembrane

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“…Showing more agreement, several independent studies recently demonstrated that PS is part of a protein complex that includes b -catenin (21± 25). Other studies that remain to be con® rmed indicate that the PS1 interacts with a brain Go-protein (26) and participates in a proteic complex associating glycogen synthase kinase-3b and its substrate tau protein (27). Both PS 1 and 2 appear to bind calsenilin, a calcium-binding protein (28), and Rab11, a GTPase enzyme involved in vesicular membrane (29).…”

Section: Presenilin S Interact With Various Proteinsmentioning

confidence: 97%