The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease
Misprocessing of amyloid precursor protein (APP) is one of the major causes of Alzheimer’s disease. APP comprises a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talins are synaptic scaffold...
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The Royal Society
2024-11-01
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| Series: | Open Biology |
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| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsob.240185 |
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| author | Charles Ellis Natasha L. Ward Matthew Rice Neil J. Ball Pauline Walle Chloé Najdek Devrim Kilinc Jean-Charles Lambert Julien Chapuis Benjamin T. Goult |
| author_facet | Charles Ellis Natasha L. Ward Matthew Rice Neil J. Ball Pauline Walle Chloé Najdek Devrim Kilinc Jean-Charles Lambert Julien Chapuis Benjamin T. Goult |
| author_sort | Charles Ellis |
| collection | DOAJ |
| description | Misprocessing of amyloid precursor protein (APP) is one of the major causes of Alzheimer’s disease. APP comprises a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talins are synaptic scaffold proteins that connect the cytoskeletal machinery to the plasma membrane via binding NPxY motifs in the cytoplasmic tail of integrins. Here, we report the crystal structure of an APP/talin1 complex identifying a new way to couple the cytoskeletal machinery to synaptic sites through APP. Proximity ligation assay (PLA) confirmed the close proximity of talin1 and APP in primary neurons, and talin1 depletion had a dramatic effect on APP processing in cells. Structural modelling reveals APP might form an extracellular meshwork that mechanically couples the cytoskeletons of the pre- and post-synaptic compartments. We propose APP processing represents a mechanical signalling pathway whereby under tension, the cleavage sites in APP have varying accessibility to cleavage by secretases. This leads us to propose a new hypothesis for Alzheimer’s, where misregulated APP dynamics result in loss of the mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of toxic plaque-forming Aβ42 peptide. |
| format | Article |
| id | doaj-art-e6eb5d9ad38545fba0cc5acd874a7f3c |
| institution | DOAJ |
| issn | 2046-2441 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj-art-e6eb5d9ad38545fba0cc5acd874a7f3c2025-08-20T02:48:09ZengThe Royal SocietyOpen Biology2046-24412024-11-01141110.1098/rsob.240185The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s diseaseCharles Ellis0Natasha L. Ward1Matthew Rice2Neil J. Ball3Pauline Walle4Chloé Najdek5Devrim Kilinc6Jean-Charles Lambert7Julien Chapuis8Benjamin T. Goult9School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UKSchool of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UKSchool of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UKSchool of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UKUniversité de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, FranceUniversité de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, FranceUniversité de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, FranceUniversité de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, FranceUniversité de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, FranceSchool of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UKMisprocessing of amyloid precursor protein (APP) is one of the major causes of Alzheimer’s disease. APP comprises a large extracellular region, a single transmembrane helix and a short cytoplasmic tail containing an NPxY motif (normally referred to as the YENPTY motif). Talins are synaptic scaffold proteins that connect the cytoskeletal machinery to the plasma membrane via binding NPxY motifs in the cytoplasmic tail of integrins. Here, we report the crystal structure of an APP/talin1 complex identifying a new way to couple the cytoskeletal machinery to synaptic sites through APP. Proximity ligation assay (PLA) confirmed the close proximity of talin1 and APP in primary neurons, and talin1 depletion had a dramatic effect on APP processing in cells. Structural modelling reveals APP might form an extracellular meshwork that mechanically couples the cytoskeletons of the pre- and post-synaptic compartments. We propose APP processing represents a mechanical signalling pathway whereby under tension, the cleavage sites in APP have varying accessibility to cleavage by secretases. This leads us to propose a new hypothesis for Alzheimer’s, where misregulated APP dynamics result in loss of the mechanical integrity of the synapse, corruption and loss of mechanical binary data, and excessive generation of toxic plaque-forming Aβ42 peptide.https://royalsocietypublishing.org/doi/10.1098/rsob.240185Alzheimer’s diseaseTLN1meshCODEamyloid precursor proteindementiaFERMT2 |
| spellingShingle | Charles Ellis Natasha L. Ward Matthew Rice Neil J. Ball Pauline Walle Chloé Najdek Devrim Kilinc Jean-Charles Lambert Julien Chapuis Benjamin T. Goult The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease Open Biology Alzheimer’s disease TLN1 meshCODE amyloid precursor protein dementia FERMT2 |
| title | The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease |
| title_full | The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease |
| title_fullStr | The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease |
| title_full_unstemmed | The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease |
| title_short | The structure of an amyloid precursor protein/talin complex indicates a mechanical basis of Alzheimer’s disease |
| title_sort | structure of an amyloid precursor protein talin complex indicates a mechanical basis of alzheimer s disease |
| topic | Alzheimer’s disease TLN1 meshCODE amyloid precursor protein dementia FERMT2 |
| url | https://royalsocietypublishing.org/doi/10.1098/rsob.240185 |
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