Conserved “PAL” sequence in presenilins is essential for γ-secretase activity, but not required for formation or stabilization of γ-secretase complexes

Wang, Jun; Brunkan, Anne L.; Hečimović, Silva; Walker, Emily; Goate, Alison M.

doi:10.1016/j.nbd.2003.12.008

Cited by 63 publications

(95 citation statements)

References 41 publications

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“…Transfection of WT-PS1 successfully restored A␤ secretion, whereas compared with transfection with WT-PS1, transfection of FAD-causing mutants (I143F-PS1 and L392V-PS1) led to A␤ secretion with an increased ratio of A␤ 42/43 to total A␤. The P433L mutant did not restore A␤ secretion, supporting the idea that P433L is a loss-of-function mutation (17,25). In contrast, the five other mutants secreted significant amounts of A␤ 42/43 while secreting only minimum or background levels of A␤ 40 .…”

Section: Identification Of Novel Endoproteolysis-impaired Ps1 Mutantsmentioning

confidence: 78%

“…Finally, like the FAD-linked mutants, P433A-PS1 was cleaved normally and exhibited a high ratio of A␤ 42/43 to total A␤. A434C and L435F (FAD-linked mutations at the neighboring residues of Pro 433 ) caused enhanced secretion of A␤ 42/43 (data not shown); and, very recently, A434D and L435R were reported to be loss-of-function mutations (25). Altogether, these results indicate that different amino acid substitutions at the same residue can result in distinct modifications of ␥-secretase activity.…”

Section: Different Amino Acid Substitutions At the Same Residue Can Rmentioning

confidence: 83%

“…Nevertheless, in most cases, except mutants harboring mutations at the cleavage site (e.g. M292D-PS1) (40,44,45), the previously reported cleavagedefective mutations simultaneously confer definitive modification of ␥-secretase activity and/or specificity (12,16,17,25,46). This is the case for PS1 LA mutants, which are distinctive in mediating exclusively ␥-43 cleavage of APP, but not self-endoproteolysis, ␥-40 cleavage, and ⑀-cleavage.…”

Section: Discussionmentioning

confidence: 93%

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Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Nakaya

Yamane

Shiraishi

et al. 2005

Journal of Biological Chemistry

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Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid ␤-peptides (A␤ 42/43 ) by altering ␥-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate ␥-secretase cleavage of the amyloid ␤-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A␤ 43 , but did not support physiological PS1 endoproteolysis or A␤ 40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A␤ 43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of ␥-secretase and that the effects of PS1 mutations and ␥-secretase inhibitors on the specificity are mediated through a common mechanism.

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Section: Identification Of Novel Endoproteolysis-impaired Ps1 Mutantsmentioning

confidence: 78%

Section: Different Amino Acid Substitutions At the Same Residue Can Rmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Nakaya

Yamane

Shiraishi

et al. 2005

Journal of Biological Chemistry

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“…1B). Formation of the NICD and likewise that of the APP intracellular domain (AICD; the counterpart of A␤) was spared by RO-02 in HEK293 cells stably coexpressing the Notch-and APP-based ␥-secretase substrates F-NEXT (16) and C99-6myc (17) up to a concentration of at least 10 M, i.e. of more than 500 times the IC 50 (A␤ 42 ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Novel γ-Secretase Enzyme Modulators Directly Target Presenilin Protein

Ebke

Luebbers

Fukumori

et al. 2011

Journal of Biological Chemistry

105

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“…NTF and CTF harbor respective YD and GxGD conserved catalytic motifs, believed to contribute to a water-containing cavity in the γ-secretase complex wherein catalysis takes place (8,9). CTF also contains a highly conserved PAL (proline, alanine, leucine) motif whose mutation leads to loss of PS activity (10,11), and which has been suggested to contribute to the active-site conformation (12) and possibly to the formation of the water-containing pore (13). The sheer size and complexity of the γ-secretase complex has made its crystallographic investigation challenging, such that the analysis of the individual components may be a complementary approach.…”

mentioning

confidence: 99%

Structural investigation of the C-terminal catalytic fragment of presenilin 1

Sobhanifar

Schneider

Löhr

et al. 2010

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

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The γ-secretase complex has a decisive role in the development of Alzheimer's disease, in that it cleaves a precursor to create the amyloid β peptide whose aggregates form the senile plaques encountered in the brains of patients. Γ-secretase is a member of the intramembrane-cleaving proteases which process their transmembrane substrates within the bilayer. Many of the mutations encountered in early onset familial Alzheimer's disease are linked to presenilin 1, the catalytic component of γ-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin 1, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin 1, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.cell-free protein expression | gamma secretase | intramembrane proteolysis | membrane protein structure A lzheimer's disease is the most common form of dementia and affects more than 25 million people worldwide. The most characteristic histological feature of Alzheimer's disease is the presence of long, insoluble amyloid fibrils composed of amyloid β (Aβ) peptide which, either alone or as reservoirs for soluble Aβ oligomers (1, 2), appear to be the primary species responsible for the massive neuronal injury presented in patients. Aβ generation is categorized under an unusual physiological phenomenon termed regulated intramembrane proteolysis. Here, the amyloid precursor protein first sheds its ectodomain mediated by β-secretase. The remaining membrane-bound C-terminal fragment is subsequently processed at a γ-cleavage site by the γ-secretase complex, a multisubunit protease whose minimal essential components include presenilin 1 (PS1) or presenilin-2 (PS2), anterior pharynx-defective, nicastrin, and presenilin enhancer 2 (3). The pathological relevance of this final step lies in the observation that γ-cleavage is variable and can occur after three distinct positions, 38, 40, and 42, whose selection influences the self-aggregating potential of the secreted Aβ peptide. Aβ42, although the minor species, appears to show the strongest potency for oligomerization and represents the majority of Aβ in amyloid plaques (4). Over 150 familial Alzheimer's disease associated mutations (www.molgen.ua.ac.be/ADMutations) have been linked to PS1, the catalyt...

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Conserved “PAL” sequence in presenilins is essential for γ-secretase activity, but not required for formation or stabilization of γ-secretase complexes

Cited by 63 publications

References 41 publications

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Random Mutagenesis of Presenilin-1 Identifies Novel Mutants Exclusively Generating Long Amyloid β-Peptides

Novel γ-Secretase Enzyme Modulators Directly Target Presenilin Protein

Structural investigation of the C-terminal catalytic fragment of presenilin 1

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