Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes

Hébert, Sébastien S.; Godin, Chantal; Tomiyama, Takami; Mori, Hiroshi; Lévesque, Georges

doi:10.1016/s0006-291x(02)02984-4

Cited by 37 publications

(36 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With 0.1% SDS, PS1 high molecular mass complex was disrupted, and some PS1 with mobility of about 90 kDa was detected, which may correspond to a subcomplex or PS1 dimer. A recent report by He´bert et al showed evidence for PS1 dimerization using 0.1% SDS treatment and alternative native electrophoresis conditions as well as by yeast two-hybrid analysis [49]. We also document that NCT migrates in BN/PAGE as a subcomplex or possible dimer stable to reducing agent and high urea concentration.…”

Section: Discussionsupporting

confidence: 77%

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

Culvenor

Ilaya

Ryan

et al. 2003

European Journal of Biochemistry

View full text Add to dashboard Cite

The presenilin proteins are required for intramembrane cleavage of a subset of type 1 membrane proteins including the Alzheimer's disease amyloid precursor protein. Previous studies indicate presenilin proteins form enzymatically active high molecular mass complexes consisting of heterodimers of N‐ and C‐terminal fragments in association with nicastrin, presenilin enhancer‐2 and anterior pharynx defective‐1 proteins. Using Blue Native gel electrophoresis (BN/PAGE) we have studied endogenous presenilin 1 complex mass, stability and association with nicastrin, presenilin enhancer‐2 and anterior pharynx defective‐1. Solubilization of mouse or human brain membranes with dodecyl‐d‐maltoside produced a 360‐kDa species reactive with antibodies to presenilin 1. Presenilin 1 complex levels were high in embryonic brain. Complex integrity was sensitive to Triton X‐100 and SDS, but stable to reducing agent. Addition of 5 m urea caused complex dissolution and nicastrin to migrate as a subcomplex. Nicastrin and presenilin enhancer‐2 were detected in the presenilin 1 complex following BN/PAGE, electroelution and second‐dimension analysis. Anterior pharynx defective‐1 was detected as an 18‐kDa form and 9‐kDa C‐terminal fragment by standard SDS/PAGE of mouse tissues, and as a predominant 36‐kDa band after presenilin 1 complex second‐dimension analysis. Membranes from brain cortex of Alzheimer's disease patients, or from cases with presenilin 1 missense mutations, indicated no change in presenilin 1 complex mobility. Higher molecular mass presenilin 1‐reactive species were detected in brain containing presenilin 1 exon 9 deletion mutation. This abnormality was confirmed using cells transfected with the same presenilin deletion mutation.

show abstract

Section: Discussionsupporting

confidence: 77%

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

Culvenor

Ilaya

Ryan

et al. 2003

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…In favor of this hypothesis, crosslinking and coimmunoprecipitation experiments suggest the presence of PS1 NT fragment homodimers in active ␥-secretase (Schroeter et al, 2003). In addition, the presence of PS1 holoprotein homodimers was suggested by a recent finding, using a yeast two-hybrid system, of the ability of PS1 to self-associate and form specific full-length/full-length homodimers (Cervantes et al, 2001(Cervantes et al, , 2004Hebert et al, 2003). Our current data suggest that the NT and CT of PS1 heterodimers come into close proximity but do not distinguish whether this is because of a PS1 single molecule ring structure or a PS1 multimer formation, and both remain plausible models.…”

Section: Discussionmentioning

confidence: 99%

Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein

Berezovska¹,

Lleó²,

Herl³

et al. 2005

J. Neurosci.

139

136

View full text Add to dashboard Cite

Presenilin 1 (PS1) is a critical component of the ␥-secretase complex, an enzymatic activity that cleaves amyloid ␤ (A␤) from the amyloid precursor protein (APP). More than 100 mutations spread throughout the PS1 molecule are linked to autosomal dominant familial Alzheimer's disease (FAD). All of these mutations lead to a similar phenotype: an increased ratio of A␤ 42 to A␤ 40, increased plaque deposition, and early age of onset. We use a recently developed microscopy approach, fluorescence lifetime imaging microscopy, to monitor the relative molecular distance between PS1 N and C termini in intact cells. We show that FAD-linked missense mutations located near the N and C termini, in the mid-region of PS1, and the exon 9 deletion mutation all change the spatial relationship between PS1 N and C termini in a similar way, increasing proximity of the two epitopes. This effect is opposite of that observed by treatment with A␤ 42 -lowering nonsteroidal anti-inflammatory drugs (NSAIDs) (Lleo et al., 2004b). Accordingly, treatment of M146L PS1-overexpressing neurons with high-dose NSAIDs somewhat offsets the conformational change associated with the mutation. Moreover, by monitoring the relative distance between a PS1 loop epitope and the APP C terminus, we demonstrate that the FAD PS1 mutations are also associated with a consistent change in the configuration of the PS1-APP complex. The nonpathogenic E318G PS1 polymorphism had no effect on PS1 N terminus-C terminus proximity or PS1-APP interactions. We propose that the conformational change we observed may therefore provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations.

show abstract

“…␥-Secretase activity is known to require at least four proteins in a complex (49-52) of 250 kDa (53), 500 kDa (54, 55), or Ͼ1,000 kDa (54, 56) depending on the detergent used. In addition, evidence that NTF and CTF homodimers can form in yeast was recently presented (57,58). If such interactions are functionally significant, the simplest complex comprising ␥-secretase could consist of two PS molecules at the catalytic site, together with Nicastrin, Aph-1, and Pen-2 at a yet-to-be-determined stoichiometry (49-52, 59, 60), possibly 2:1:1:1 (Ϸ250 kDa) or 2:2:2:2 (Ͼ250 kDa).…”

Section: Ps Could Act As a Dimermentioning

confidence: 99%

A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis

Schroeter

Ilagan²,

Brunkan³

et al. 2003

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

196

View full text Add to dashboard Cite

Notch receptors and the amyloid precursor protein are type I membrane proteins that are proteolytically cleaved within their transmembrane domains by a presenilin (PS)-dependent ␥-secretase activity. In both proteins, two peptide bonds are hydrolyzed: one near the inner leaflet and the other in the middle of the transmembrane domain. Under saturating conditions the substrates compete with each other for proteolysis, but not for binding to PS. At least some Alzheimer's disease-causing PS mutations reside in proteins possessing low catalytic activity. We demonstrate (i) that differentially tagged PS molecules coimmunoprecipitate, and (ii) that PS N-terminal fragment dimers exist by using a photoaffinity probe based on a transition state analog ␥-secretase inhibitor. We propose that ␥-secretase contains a PS dimer in its catalytic core, that binding of substrate is at a site separate from the active site, and that substrate is cleaved at the interface of two PS molecules.

show abstract

Dimerization of presenilin-1 in vivo: suggestion of novel regulatory mechanisms leading to higher order complexes

Cited by 37 publications

References 38 publications

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

Characterization of presenilin complexes from mouse and human brain using Blue Native gel electrophoresis reveals high expression in embryonic brain and minimal change in complex mobility with pathogenic presenilin mutations

Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein

A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis

Contact Info

Product

Resources

About