Evidence that the COOH terminus of human presenilin 1 is located in extracytoplasmic space

Oh, Young S.; Turner, R

doi:10.1152/ajpcell.00636.2004

Cited by 18 publications

(18 citation statements)

References 32 publications

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“…The ER-retention signal of PS1 is probably embedded in the membrane, as a number of groups recently showed that the hydrophobic part of the PS1 C-terminus spans the membrane. This suggests a topology with nine TMDs for PS [8][9][10] . In the case of PEN-2, the retention/retrieval signal is located in TMD1 and involves a critical asparagine [Kaether et al, submitted].…”

Section: Assembly Of the ␥ -Secretase Complexmentioning

confidence: 89%

“…The responsible genes, termed presenilin 1 (PS1) and presenilin 2 (PS2) were predicted to encode two homologous ϳ 50-kDa polytopic membrane proteins, that according to recent models consist of 9 transmembrane domains (TMDs) [8][9][10] . Both are endoproteolytically cleaved between TMDs 6 and 7 into an N-terminal and C-terminal fragment (NTF, CTF) [11] .…”

Section: Identification Of ␥ -Secretasementioning

confidence: 99%

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Assembly, Trafficking and Function of γ-Secretase

Kaether¹,

Haass²,

Steiner³

2006

Neurodegener Dis

147

115

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γ-Secretase catalyzes the final cleavage of the β-amyloid precursor protein to generate amyloid-β peptide, the principal component of amyloid plaques in the brains of patients suffering from Alzheimer’s disease. Here, we review the identification of γ-secretase as a protease complex and its assembly and trafficking to its site(s) of cellular function. In reconstitution experiments, γ-secretase was found to be composed of four integral membrane proteins, presenilin (PS), nicastrin (NCT), PEN-2 and APH-1 that are essential and sufficient for γ-secretase activity. PS, which serves as a catalytic subunit of γ-secretase, was identified as a prototypic member of novel aspartyl proteases of the GxGD type. In human cells, γ-secretase could be further defined as a heterogeneous activity consisting of distinct complexes that are composed of PS1 or PS2 and APH-1a or APH-1b homologues together with NCT and PEN-2. Using green fluorescent protein as a reporter we localized PS and γ-secretase activity at the plasma membrane and endosomes. Investigation of γ-secretase complex assembly in knockdown and knockout cells of the individual subunits allowed us to develop a model of complex assembly in which NCT and APH-1 first stabilize PS before PEN-2 assembles as the last component. Furthermore, we could map domains in PS and PEN-2 that govern assembly and trafficking of the complex. Finally, Rer1 was identified as a PEN-2-binding protein that serves a role as an auxiliary factor for γ-secretase complex assembly.

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Section: Assembly Of the ␥ -Secretase Complexmentioning

confidence: 89%

Section: Identification Of ␥ -Secretasementioning

confidence: 99%

Assembly, Trafficking and Function of γ-Secretase

Kaether¹,

Haass²,

Steiner³

2006

Neurodegener Dis

147

115

View full text Add to dashboard Cite

show abstract

“…Recently, however, several cell-based topological studies revealed that the hydrophobic region 9 (I408 -F428) and 10 (A434 -V453) of PS1 (Henricson et al, 2005) penetrate the membrane as TMD8 and TMD9, respectively, and that the extreme C terminus is exposed to the extracellular/luminal side (Laudon et al, 2005;Oh and Turner, 2005;Spasic et al, 2006). Moreover, the PAL motif that resides at the N-terminal region of the hydrophobic region 10 is highly conserved in PS and SPP proteins and is required for the enzymatic activity (Tomita et al, 2001;Wang et al, 2004;Nakaya et al, 2005;J.…”

Section: Scam Analysis Of Hydrophobic Region 9 and The Pal Motif Of Ps1mentioning

confidence: 99%

The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the -Secretase

Sato

Takagi²,

Tomita³

et al. 2008

Journal of Neuroscience

143

166

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␥-Secretase is an unusual membrane-embedded protease, which cleaves the transmembrane domains (TMDs) of type I membrane proteins, including amyloid-␤ precursor protein and Notch receptor. We have previously shown the existence of a hydrophilic pore formed by TMD6 and TMD7 of presenilin 1 (PS1), the catalytic subunit of ␥-secretase, within the membrane by the substituted cysteine accessibility method. Here we analyzed the structure of TMD8, TMD9, and the C terminus of PS1, which encompass the conserved PAL motif and the hydrophobic C-terminal tip, both being critical for the catalytic activity and the formation of the ␥-secretase complex. We found that the amino acid residues around the PAL motif and the extracellular/luminal portion of TMD9 are highly water accessible and located in proximity to the catalytic pore. Furthermore, the region starting from the luminal end of TMD9 toward the C terminus forms an amphipathic ␣-helix-like structure that extends along the interface between the membrane and the extracellular milieu. Competition analysis using ␥-secretase inhibitors revealed that the TMD9 is involved in the initial binding of substrates, as well as in the subsequent catalytic process as a subsite. Our results provide mechanistic insights into the role of TMD9 in the formation of the catalytic pore and the substrate entry, crucial to the unusual mode of intramembrane proteolysis by ␥-secretase.

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“…The active site aspartate residues are displayed in red. PS is depicted according to the recent nine TMD model (Henricson et al, 2005;Laudon et al, 2005;Oh and Turner, 2005).…”

Section: Ps1/spe-4 6/7 Is Deficient In Notch Signalingmentioning

confidence: 99%

The GxGD Motif of Presenilin Contributes to Catalytic Function and Substrate Identification of γ-Secretase

Yamasaki¹,

Eimer²,

Okochi³

et al. 2006

J. Neurosci.

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␥-Secretase is a multisubunit aspartyl protease complex that catalyzes intramembrane cleavage of ␤-amyloid precursor protein (APP), a substrate key to Alzheimer's disease pathogenesis, and of Notch, a substrate crucial for cell differentiation. How ␥-secretase recognizes and selects substrates is currently barely understood. Recent data suggest that its subunit nicastrin serves as an initial substrate receptor, which might subsequently forward substrates to the active site domain located in its catalytic subunit presenilin (PS), where an additional substrate binding site has been proposed. We now used an active site domain swapping approach of PS1 with its most distant homolog, spermatogenesis defective (SPE-4), to identify sequence determinants in this region. Strikingly, when the active site domain of PS1 was exchanged with that of SPE-4, the chimeric protein, PS1/SPE-4 6/7 , supported APP but not Notch processing. In addition, PS1/SPE-4 6/7 was strongly impaired in Caenorhabditis elegans Notch signaling in vivo. Mapping experiments identified a single amino acid at position x of the GxGD motif, which contains one of the two active site aspartates, to be responsible for the observed defect in Notch processing and signaling. Our data thus implicate a role of the GxGD motif in catalytic function and substrate identification of ␥-secretase.

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Evidence that the COOH terminus of human presenilin 1 is located in extracytoplasmic space

Cited by 18 publications

References 32 publications

Assembly, Trafficking and Function of γ-Secretase

Assembly, Trafficking and Function of γ-Secretase

The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the -Secretase

The GxGD Motif of Presenilin Contributes to Catalytic Function and Substrate Identification of γ-Secretase

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