Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization
Summary: Amyloid precursor protein (APP) cleavage by the β-secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimer...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004220310841 |
| _version_ | 1818594552570707968 |
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| author | Florian Perrin Nicolas Papadopoulos Nuria Suelves Rémi Opsomer Devkee M. Vadukul Céline Vrancx Steven O. Smith Didier Vertommen Pascal Kienlen-Campard Stefan N. Constantinescu |
| author_facet | Florian Perrin Nicolas Papadopoulos Nuria Suelves Rémi Opsomer Devkee M. Vadukul Céline Vrancx Steven O. Smith Didier Vertommen Pascal Kienlen-Campard Stefan N. Constantinescu |
| author_sort | Florian Perrin |
| collection | DOAJ |
| description | Summary: Amyloid precursor protein (APP) cleavage by the β-secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled-coil to the C99 TM domain, the dimer containing the 33Gly-x-x-x-Gly37 motif in the interface promoted the Aβ42 processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the 25Gly-x-x-x-Gly29 motif in the interface favored processing to Aβ43/40. It induced significantly less gene transcription, while promoting formation of SDS-resistant “Aβ-like” oligomers, reminiscent of Aβ peptide oligomers. These required both Val24 of a pro-β motif and the 25Gly-x-x-x-Gly29 interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ48 or Aβ49, linking the former to enhanced signaling and Aβ42 production. |
| first_indexed | 2024-12-16T11:01:56Z |
| format | Article |
| id | doaj.art-0dd44fb254d34538a6340aed44bc05be |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-12-16T11:01:56Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-0dd44fb254d34538a6340aed44bc05be2022-12-21T22:33:59ZengElsevieriScience2589-00422020-12-012312101887Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and OligomerizationFlorian Perrin0Nicolas Papadopoulos1Nuria Suelves2Rémi Opsomer3Devkee M. Vadukul4Céline Vrancx5Steven O. Smith6Didier Vertommen7Pascal Kienlen-Campard8Stefan N. Constantinescu9Ludwig Cancer Research, Brussels 1200, Belgium; Welbio, SIGN Unit, de Duve Institute, UCLouvain, Brussels, 1200, Belgium; Institute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumLudwig Cancer Research, Brussels 1200, Belgium; Welbio, SIGN Unit, de Duve Institute, UCLouvain, Brussels, 1200, Belgium; Institute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumInstitute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumInstitute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumInstitute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumInstitute of Neurosciences (IoNS), UCLouvain, Brussels 1200, BelgiumDepartment of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215, USAMass Spectrometry Platform, de Duve Institute, UCLouvain, Brussels, 1200 BelgiumInstitute of Neurosciences (IoNS), UCLouvain, Brussels 1200, Belgium; Corresponding authorLudwig Cancer Research, Brussels 1200, Belgium; Welbio, SIGN Unit, de Duve Institute, UCLouvain, Brussels, 1200, Belgium; Corresponding authorSummary: Amyloid precursor protein (APP) cleavage by the β-secretase produces the C99 transmembrane (TM) protein, which contains three dimerization-inducing Gly-x-x-x-Gly motifs. We demonstrate that dimeric C99 TM orientations regulate the precise cleavage lines by γ-secretase. Of all possible dimeric orientations imposed by a coiled-coil to the C99 TM domain, the dimer containing the 33Gly-x-x-x-Gly37 motif in the interface promoted the Aβ42 processing line and APP intracellular domain-dependent gene transcription, including the induction of BACE1 mRNA, enhancing amyloidogenic processing and signaling. Another orientation exhibiting the 25Gly-x-x-x-Gly29 motif in the interface favored processing to Aβ43/40. It induced significantly less gene transcription, while promoting formation of SDS-resistant “Aβ-like” oligomers, reminiscent of Aβ peptide oligomers. These required both Val24 of a pro-β motif and the 25Gly-x-x-x-Gly29 interface. Thus, crossing angles imposed by precise dimeric orientations control γ-secretase initial cleavage at Aβ48 or Aβ49, linking the former to enhanced signaling and Aβ42 production.http://www.sciencedirect.com/science/article/pii/S2589004220310841Biological SciencesBiochemistryMolecular BiologyNeuroscience |
| spellingShingle | Florian Perrin Nicolas Papadopoulos Nuria Suelves Rémi Opsomer Devkee M. Vadukul Céline Vrancx Steven O. Smith Didier Vertommen Pascal Kienlen-Campard Stefan N. Constantinescu Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization iScience Biological Sciences Biochemistry Molecular Biology Neuroscience |
| title | Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization |
| title_full | Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization |
| title_fullStr | Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization |
| title_full_unstemmed | Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization |
| title_short | Dimeric Transmembrane Orientations of APP/C99 Regulate γ-Secretase Processing Line Impacting Signaling and Oligomerization |
| title_sort | dimeric transmembrane orientations of app c99 regulate γ secretase processing line impacting signaling and oligomerization |
| topic | Biological Sciences Biochemistry Molecular Biology Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004220310841 |
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