Supporting evidence for the existence of a molecular species of presenilin 1 with a seven membrane-spanning and one membrane-embedded structure

Nakai, Toshiki; Hagi, Tomomi; Miura, Satoshi

doi:10.1016/s0197-4580(00)82886-9

Cited by 17 publications

(33 citation statements)

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“…Early topological reports were based on gene fusion studies in which truncated versions of PS1 were fused to reporter proteins that could be modified according to their cytoplasmic or extracytoplasmic locations. These studies yielded six (18), seven (17), and eight (15, 56) TMS models of PS1, where CTF was predicted to contain from zero to two transmembrane helices. This inconsistency owes likely to the approach, which may suffer from artifacts related to truncation and the nature of reporter proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The NTF, in consensus with all published models, is believed to have a classical transmembrane topology consisting of six α-helices. In contrast, the models proposed for CTF topology vary greatly and are often irreconcilable (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). The most accepted PS1 model maintains a nine transmembrane segment (TMS) topology, three of which reside in CTF (14,21,22).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Previous computational predictions and cell-based topological studies indicated that the hydrophobic region (HR) 1 of PS1 spans the membrane as TMD1 (Doan et al, 1996;Li and Greenwald, 1996;Lehmann et al, 1997;Nakai et al, 1999). To examine whether this region penetrates the membrane as a TMD and faces to the aqueous environment in the lipid bilayer, we constructed mutant PS1 having a single cysteine residue based on PS1/Cys(Ϫ) (single-Cys mt PS1) at 32 different amino acid residues in and around the HR1 (E71-V103), and expressed them in DKO cells (Fig.…”

Section: Scam Analysis Of the Hydrophobic Region 1 Of Ps1mentioning

confidence: 99%

Participation of Transmembrane Domain 1 of Presenilin 1 in the Catalytic Pore Structure of the γ-Secretase

Takagi

Tominaga²,

Sato³

et al. 2010

J. Neurosci.

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␥-Secretase is an intramembrane-cleaving protease that is responsible for the generation of amyloid-␤ peptides linked to the pathogenesis of Alzheimer's disease. Using a substituted cysteine accessibility method, we have previously shown that the hydrophilic "catalytic pore" structure of ␥-secretase is formed by the transmembrane domains (TMDs) 6, 7, and 9 of presenilin 1 (PS1), the catalytic subunit of ␥-secretase, within the membrane. Here, we analyzed the structure in and around the first hydrophobic region, the putative TMD1, of PS1, of which the precise function as well as three-dimensional location within ␥-secretase remained unknown. We found that TMD1 is located in proximity to the catalytic GxGD and PAL motifs within the C-terminal fragment of PS1, facing directly the catalytic pore. Competition experiments using known ␥-secretase inhibitors suggested that the N-terminal region of TMD1 functions as a subsite during proteolytic action of the ␥-secretase. Intriguingly, binding of inhibitors affected water accessibility of residues at the membrane border of TMD1, suggesting the possibility of a dynamic motion of TMD1 during the catalytic process. Our results provide mechanistic insights into the functional role of TMD1 of PS1 in the intramembrane-cleaving activity of the ␥-secretase.

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“…1A). Essentially two types of studies have been performed by various groups to study the PS1 topology: experiments examining antibody epitope accessibility before and after plasma membrane permeabilization (5)(6)(7)(8), and experiments examining the membrane integration of truncated forms of PS1 (17,21) or SEL-12 (18,19), a PS1 homologue from C. elegans. In these latter experiments reporter peptides were fused to PS1 or SEL-12 truncated after each HR and these chimeric proteins were expressed in isolated microsomes or intact cells.…”

Section: Introductionmentioning

confidence: 99%

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

Turner

2005

American Journal of Physiology-Cell Physiology

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The polytopic membrane protein presenilin 1 (PS1) is a component of the γ-secretase complex that is responsible for the intramembranous cleavage of a number of type I transmembrane proteins including the β-amyloid precursor protein (APP). Mutations of PS1, apparently leading to aberrant processing of APP, have been genetically linked to early-onset familial Alzheimer's disease. PS1 contains ten hydrophobic regions (HRs) sufficiently long to be α-helical membrane spanning segments. Most topology models for PS1 place its C-terminal ∼40 amino acids, which include the 10 th HR, in the cytosolic space. However, several recent observations suggest that HR 10 may be integrated into the membrane and involved in the interaction between PS1 and APP. We have applied three independent methodologies to investigate the location of HR 10 and the extreme C-terminus of PS1. The results from these methods indicate that HR 10 spans the membrane and that the Cterminal amino acids of PS1 lie in the extra-cytoplasmic space.

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Supporting evidence for the existence of a molecular species of presenilin 1 with a seven membrane-spanning and one membrane-embedded structure

Cited by 17 publications

References 0 publications

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

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

Participation of Transmembrane Domain 1 of Presenilin 1 in the Catalytic Pore Structure of the γ-Secretase

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

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