Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction
Mutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
1999-02-01
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| Series: | Neurobiology of Disease |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996198902121 |
| _version_ | 1818648752292888576 |
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| author | Laurent Pradier Nathalie Carpentier Laurence Delalonde Nicole Clavel Marie-Dominique Bock Luc Buée Luc Mercken Bruno Tocqué Christian Czech |
| author_facet | Laurent Pradier Nathalie Carpentier Laurence Delalonde Nicole Clavel Marie-Dominique Bock Luc Buée Luc Mercken Bruno Tocqué Christian Czech |
| author_sort | Laurent Pradier |
| collection | DOAJ |
| description | Mutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we confirmed this interaction and have mapped the interaction domains on both PS2 and APP. Using several carboxy-terminal truncated forms of PS2, we demonstrated that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) was sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpart was shown to interact with APP. For APP, we could demonstrate interaction of PS2 with the last 100 but not the last 45 amino acids of APP, including therefore the Aβ region. Accordingly, SecPS2NT is capable of binding to Aβ-immunoreactive species in conditioned medium. In addition, a second region in the extracellular domain of APP also interacted with PS2. Comparable results with PS1 indicate that the two presenilins share similar determinants of binding to APP. Confirming these results, SecPS2NT is able to inhibit PS1/APP interaction. Such a competition makes it unlikely that the PS/APP interaction results from nonspecific aggregation of PS in transfected cells. The physical interaction of presenilins with a region encompassing the Aβ sequence of APP could be causally related to the misprocessing of APP and the production of Aβ1-42. |
| first_indexed | 2024-12-17T01:23:25Z |
| format | Article |
| id | doaj.art-e74a0eab420d4e09aca715f3a9c305c5 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T01:23:25Z |
| publishDate | 1999-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e74a0eab420d4e09aca715f3a9c305c52022-12-21T22:08:45ZengElsevierNeurobiology of Disease1095-953X1999-02-01614355Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 InteractionLaurent Pradier0Nathalie Carpentier1Laurence Delalonde2Nicole Clavel3Marie-Dominique Bock4Luc Buée5Luc Mercken6Bruno Tocqué7Christian Czech8Gene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceGene Medicine Department, Rhône-Poulenc Rorer, 94400, Vitry, France; INSERM U422, 59045, Lille, FranceMutations in presenilin 1 and presenilin 2 (PS1 and PS2, respectively) genes cause the large majority of familial forms of early-onset Alzheimer's disease. The physical interaction between presenilins and APP has been recently described using coimmunoprecipitation. With a similar technique, we confirmed this interaction and have mapped the interaction domains on both PS2 and APP. Using several carboxy-terminal truncated forms of PS2, we demonstrated that the hydrophilic amino terminus of PS2 (residues 1 to 87, PS2NT) was sufficient for interaction with APP. Interestingly, only a construct with a leader peptide for secretion (SecPS2NT) and not its cytosolic counterpart was shown to interact with APP. For APP, we could demonstrate interaction of PS2 with the last 100 but not the last 45 amino acids of APP, including therefore the Aβ region. Accordingly, SecPS2NT is capable of binding to Aβ-immunoreactive species in conditioned medium. In addition, a second region in the extracellular domain of APP also interacted with PS2. Comparable results with PS1 indicate that the two presenilins share similar determinants of binding to APP. Confirming these results, SecPS2NT is able to inhibit PS1/APP interaction. Such a competition makes it unlikely that the PS/APP interaction results from nonspecific aggregation of PS in transfected cells. The physical interaction of presenilins with a region encompassing the Aβ sequence of APP could be causally related to the misprocessing of APP and the production of Aβ1-42.http://www.sciencedirect.com/science/article/pii/S0969996198902121 |
| spellingShingle | Laurent Pradier Nathalie Carpentier Laurence Delalonde Nicole Clavel Marie-Dominique Bock Luc Buée Luc Mercken Bruno Tocqué Christian Czech Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction Neurobiology of Disease |
| title | Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction |
| title_full | Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction |
| title_fullStr | Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction |
| title_full_unstemmed | Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction |
| title_short | Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 Interaction |
| title_sort | mapping the app presenilin ps binding domains the hydrophilic n terminus of ps2 is sufficient for interaction with app and can displace app ps1 interaction |
| url | http://www.sciencedirect.com/science/article/pii/S0969996198902121 |
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