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The Journal of Biological Chemistry Sep 2006Presenilin-1 is a polytopic membrane protein that assembles with nicastrin, PEN-2, and APH-1 into an active gamma-secretase complex required for intramembrane...
Presenilin-1 is a polytopic membrane protein that assembles with nicastrin, PEN-2, and APH-1 into an active gamma-secretase complex required for intramembrane proteolysis of type I transmembrane proteins. Although essential for a correct understanding of structure-function relationships, its exact topology remains an issue of strong controversy. We revisited presenilin-1 topology by inserting glycosylation consensus sequences in human PS1 and expressing the obtained mutants in a presenilin-1 and 2 knock-out background. Based on the glycosylation status of these variants we provide evidence that presenilin-1 traffics through the Golgi after a conformational change induced by complex assembly. Based on our glycosylation variants of presenilin-1 we hypothesize that complex assembly occurs during transport between the endoplasmic reticulum and the Golgi apparatus. Furthermore, our data indicate that presenilin-1 has a nine-transmembrane domain topology with the COOH terminus exposed to the lumen/extracellular surface. This topology is independently underscored by lysine mutagenesis, cell surface biotinylation, and cysteine derivation strategies and is compatible with the different physiological functions assigned to presenilin-1.
Topics: Amyloid Precursor Protein Secretases; Animals; Glycosylation; HeLa Cells; Humans; Mice; Mice, Knockout; Models, Molecular; Presenilin-1; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 16846981
DOI: 10.1074/jbc.M600592200 -
PloS One Apr 2011Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic...
Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS-/- cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD.
Topics: Amyloid Precursor Protein Secretases; Animals; Brain; Calcium-Binding Proteins; Chickens; Gene Expression Regulation, Enzymologic; Humans; Lentivirus; Mice; Models, Biological; Neural Cell Adhesion Molecules; Neurons; Presenilins; Rats; Receptors, Cell Surface; Synapses
PubMed: 21559374
DOI: 10.1371/journal.pone.0019430 -
Aging Clinical and Experimental Research Jun 2021Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly. Few cases are familial (FAD), due to autosomal dominant mutations in presenilin-1 (PS1),...
Alzheimer's disease (AD) is the most frequent cause of dementia in the elderly. Few cases are familial (FAD), due to autosomal dominant mutations in presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP). The three proteins are involved in the generation of amyloid-beta (Aβ) peptides, providing genetic support to the hypothesis of Aβ pathogenicity. However, clinical trials focused on the Aβ pathway failed in their attempt to modify disease progression, suggesting the existence of additional pathogenic mechanisms. Ca dysregulation is a feature of cerebral aging, with an increased frequency and anticipated age of onset in several forms of neurodegeneration, including AD. Interestingly, FAD-linked PS1 and PS2 mutants alter multiple key cellular pathways, including Ca signaling. By generating novel tools for measuring Ca in living cells, and combining different approaches, we showed that FAD-linked PS2 mutants significantly alter cell Ca signaling and brain network activity, as summarized below.
Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Brain; Homeostasis; Humans; Presenilin-1; Presenilin-2
PubMed: 31606858
DOI: 10.1007/s40520-019-01341-0 -
Current Alzheimer Research Apr 2008Mutations in the presenilin 1 (PS1) gene are the major cause of familial Alzheimer s disease (AD). They effect an increased production of the highly neurotoxic 42 amino... (Review)
Review
Mutations in the presenilin 1 (PS1) gene are the major cause of familial Alzheimer s disease (AD). They effect an increased production of the highly neurotoxic 42 amino acid variant of the amyloid-beta peptide (Abeta), which is believed to initiate the disease. Abeta is the product of two consecutive cleavages of the beta-amyloid precursor protein (APP) by two proteases, beta-secretase and gamma-secretase. The latter enzyme has been identified as an intramembrane-cleaving multiprotein complex that apart from APP cleaves a large number of other type I transmembrane proteins. PS1 and its homologue PS2 are essential for gamma-secretase cleavage and more than a decade after their discovery it is now firmly established that they function as catalytic subunits of gamma-secretase. This review recapitulates the findings that led to this conclusion as well as the further progress made on the function of PS as gamma-secretase since then.
Topics: Amino Acid Sequence; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Binding Sites; Catalysis; Humans; Molecular Sequence Data; Presenilins; Receptors, Notch; Substrate Specificity
PubMed: 18393799
DOI: 10.2174/156720508783954677 -
Neurobiology of Aging Dec 2019Presenilin 1 (PSEN1) is a γ-secretase component, which is in charge of the amyloid precursor protein (APP) cleavage. APP is believed to play a central role in the...
Presenilin 1 (PSEN1) is a γ-secretase component, which is in charge of the amyloid precursor protein (APP) cleavage. APP is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). PSEN1 mutations are the most important causes of familial AD, being related to the earlier onset and rapid progression of the disease. Presenilins and APP mutations represent an extraordinary opportunity to study the pathophysiology of AD. We describe the clinical and genetic study of a 37-year-old male patient with a novel mutation in PSEN1 (p.Thr-Pro116-117Ser-Thr). We have studied the pedigree of his family with a further 9 members affected, all of them with onset in their 30s. We have also described the clinical data and results of brain biopsies in 2 of them. DNA sequencing of a tissue sample from an uncle of the patient, who died of AD in the 80s, showed the same mutation as in the patient. These data and predictive analysis indicate the pathogenicity of the mutation.
Topics: Alzheimer Disease; Humans; Mutation; Presenilin-1
PubMed: 31204041
DOI: 10.1016/j.neurobiolaging.2019.05.012 -
Cell Stress & Chaperones Dec 2008Familial Alzheimer's disease (FAD)-linked presenilin (PS) mutations show gain-of-toxic-function characteristics. These FAD PS mutations are scattered throughout the PS... (Review)
Review
Familial Alzheimer's disease (FAD)-linked presenilin (PS) mutations show gain-of-toxic-function characteristics. These FAD PS mutations are scattered throughout the PS molecule, reminiscent of the distribution of cystic fibrosis transmembrane conductance regulator and p53 mutations. Because of the scattered distribution of PS mutations, it is difficult to infer mechanistic insights about how these mutations cause the disease similarly. Recent careful reexamination of gamma-secretase activity indicates that some PS mutations decrease the proteolytic activity of gamma-secretase, suggesting a loss-of-function nature of PS mutations. To extend this observation to all known PS mutations, a large number of PS mutations were evaluated using bioinformatic tools. The analyses reveal that as many as one third of PS1 residues are highly conserved, that about 75% of FAD mutations are located to the highly conserved residues, and that most PS mutations likely damage the activity of PS. These results are consistent with the idea that the majority of PS mutations lower the activity of PS/gamma-secretase.
Topics: Alzheimer Disease; Amino Acid Sequence; Conserved Sequence; Humans; Molecular Sequence Data; Mutation; Presenilins; Protein Folding; Sequence Analysis, DNA
PubMed: 18491041
DOI: 10.1007/s12192-008-0046-0 -
Journal of Biomolecular Structure &... Jul 2020Presenilins 1 and 2 (PS1 or PS2) are main genetic risk factors of familial Alzheimer's disease (AD) that produce the β-amyloid (Aβ) peptides and also have important...
Presenilins 1 and 2 (PS1 or PS2) are main genetic risk factors of familial Alzheimer's disease (AD) that produce the β-amyloid (Aβ) peptides and also have important stand-alone functions related to, e.g. calcium signaling. Most work so far has focused on PS1, but humans carry both PS1 and PS2, and mutations in both cause AD. Here, we develop a computational model of PS2 in the membrane to address the question how pathogenic PS2 mutations affect the membrane-embedded protein. The models are based on cryo-electron microscopy structures of PS1 translated to PS2, augmented with missing residues and a complete all-atom membrane-water system, and equilibrated using three independent 500-ns simulations of molecular dynamics with a structure-balanced force field. We show that the nine-transmembrane channel structure is substantially controlled by major dynamics in the hydrophilic loop bridging TM6 and TM7, which functions as a 'plug' in the PS2 membrane channel. TM2, TM6, TM7 and TM9 flexibility controls the size of this channel. We find that most pathogenic PS2 mutations significantly reduce stability relative to random mutations, using a statistical ANOVA test with all possible mutations in the affected sites as a control. The associated loss of compactness may also impair calcium affinity. Remarkably, similar properties of the open state are known to impair the binding of substrates to γ-secretase, and we thus argue that the two mechanisms could be functionally related.Communicated by Ramaswamy H. Sarma.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Cryoelectron Microscopy; Humans; Molecular Dynamics Simulation; Presenilin-1; Presenilin-2
PubMed: 31405326
DOI: 10.1080/07391102.2019.1655481 -
Differentiation; Research in Biological... 2018Presenilins (Psen1 and Psen2 in mice) are polytopic transmembrane proteins that act in the γ-secretase complex to make intra-membrane cleavages of their substrates,...
Presenilins (Psen1 and Psen2 in mice) are polytopic transmembrane proteins that act in the γ-secretase complex to make intra-membrane cleavages of their substrates, including the well-studied Notch receptors. Such processing releases the Notch intracellular domain, allowing it to physically relocate from the cell membrane to the nucleus where it acts in a transcriptional activating complex to regulate downstream genes in the signal-receiving cell. Previous studies of Notch pathway mutants for Jagged1, Notch2, and Rbpj demonstrated that canonical signaling is a necessary component of normal mouse lens development. However, the central role of Psens within the γ-secretase complex has never been explored in any developing eye tissue or cell type. By directly comparing Psen single and double mutant phenotypes during mouse lens development, we found a stronger requirement for Psen1, although both genes are needed for progenitor cell growth and to prevent apoptosis. We also uncovered a novel genetic interaction between Psen1 and Jagged1. By quantifying protein and mRNA levels of key Notch pathway genes in Psen1/2 or Jagged1 mutant lenses, we identified multiple points in the overall signaling cascade where feedback regulation can occur. Our data are consistent with the loss of particular genes indirectly influencing the transcription level of another. However, we conclude that regulating Notch2 protein levels is particularly important during normal signaling, supporting the importance of post-translational regulatory mechanisms in this tissue.
Topics: Animals; Cell Cycle; Cell Membrane; Lens, Crystalline; Mice, Transgenic; Presenilins; Receptor, Notch2; Receptors, Notch; Signal Transduction
PubMed: 30059908
DOI: 10.1016/j.diff.2018.07.003 -
The Journal of Biological Chemistry Jul 2011Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I...
Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through γ-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via γ-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither γ-secretase activity nor Wnt/β-catenin signaling can reduce the expression of IR, but a PS-mediated increase in the intracellular Ca(2+) level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.
Topics: Amyloid Precursor Protein Secretases; Animals; Calcium; Calcium Signaling; Cells, Cultured; Gene Expression Regulation; Insulin; Mice; Mice, Knockout; Presenilins; Receptor, Insulin; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 21622565
DOI: 10.1074/jbc.M111.248922 -
Journal of Immunology (Baltimore, Md. :... Jan 2010CD46 is a type I transmembrane protein with complement and T cell regulatory functions in human cells. CD46 has signaling and receptor properties in immune and nonimmune...
CD46 is a type I transmembrane protein with complement and T cell regulatory functions in human cells. CD46 has signaling and receptor properties in immune and nonimmune cells, many of which are dependent on the expression of cytoplasmic tail (cyt) isoforms cyt1 or cyt2. Little is known about how cyt1 and cyt2 mediate cellular responses. We show that CD46-cyt1 and CD46-cyt2 are substrates for presenilin/gamma-secretase (PS/gammaS), an endogenous protease complex that regulates many important signaling proteins through proteolytic processing. PS/gammaS processing of CD46 releases immunoprecipitable cyt1 and cyt2 tail peptides into the cell, is blocked by chemical inhibitors, and is prevented in dominant negative presenilin mutant cell lines. Two human pathogens, Neisseria gonorrhoeae and Neisseria meningitidis, stimulate PS/gammaS processing of CD46-cyt1 and CD46-cyt2. This stimulation requires type IV pili and PilT, the type IV pilus retraction motor, implying that mechanotransduction plays a role in this event. We present a model for PS/gammaS processing of CD46 that provides a mechanism by which signals are transduced via the cyt1 and cyt2 tails to regulate CD46-dependent cellular responses. Our findings have broad implications for understanding the full range of CD46 functions in infection and noninfection situations.
Topics: Amyloid Precursor Protein Secretases; Fimbriae, Bacterial; Gonorrhea; Humans; Mechanotransduction, Cellular; Membrane Cofactor Protein; Meningococcal Infections; Neisseria gonorrhoeae; Neisseria meningitidis; Presenilins; Protein Isoforms; Signal Transduction
PubMed: 20018629
DOI: 10.4049/jimmunol.0900522