المؤلفون: Wim Annaert, Katleen Dillen, Randy Schekman, Ragna Sannerud, Bertrand Kleizen, Rosanne Wouters, David Demedts, Christine Michiels, Abril Escamilla Ayala, Wendy Vermeire

المصدر: Journal of Cell Biology, 220(9), 1. Rockefeller University Press

مصطلحات موضوعية: Models, Molecular, Endopeptidases/chemistry, Protein Conformation, Vesicular Transport Proteins, Wistar, Golgi Apparatus, Endoplasmic Reticulum, Mice, Neurons/cytology, 0302 clinical medicine, COP-Coated Vesicles/chemistry, Models, COMPLEX COMPONENT, PSEN1, Protein Isoforms, Endoplasmic Reticulum/metabolism, COPII, Cerebral Cortex, Neurons, Golgi Apparatus/metabolism, 0303 health sciences, Budding, Tumor, biology, MEMBRANE-PROTEINS, Vesicle, ER RETENTION, Cell biology, AMYLOID PRECURSOR PROTEIN, ALZHEIMERS-DISEASE, COP-Coated Vesicles, Life Sciences & Biomedicine, Cerebral Cortex/cytology, Protein Binding, Signal Transduction, STRUCTURAL BASIS, COPII VESICLES, PRESENILIN-1, Protein subunit, Primary Cell Culture, Protein Isoforms/chemistry, Nicastrin, Amyloid Precursor Protein Secretases/chemistry, Presenilin, Cell Line, Vesicular Transport Proteins/genetics, 03 medical and health sciences, QUALITY-CONTROL, Cell Line, Tumor, Presenilin-1/chemistry, Endopeptidases, Presenilin-1, Animals, Humans, Rats, Wistar, 030304 developmental biology, Science & Technology, Endoplasmic reticulum, Membrane Proteins, Molecular, Membrane Proteins/chemistry, Biological Transport, Cell Biology, Fibroblasts, Rats, Fibroblasts/cytology, Gene Expression Regulation, biology.protein, INTERMEDIATE COMPARTMENT, Amyloid Precursor Protein Secretases, Protein Multimerization, 030217 neurology & neurosurgery

الوصف: γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer's disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in post-Golgi compartments. ispartof: JOURNAL OF CELL BIOLOGY vol:220 issue:9 ispartof: location:United States status: published

وصف الملف: application/pdf; Print-Electronic

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::09d9039d96590f096bfacb0662aeabdbTest
https://doi.org/10.1083/jcb.201911104Test

المؤلفون: Wim Annaert, Abril Escamilla-Ayala, Rosanne Wouters, Ragna Sannerud

المصدر: Seminars in celldevelopmental biology. 105

مصطلحات موضوعية: 0301 basic medicine, Inhibitor, Interactor, Assembly, Nicastrin, Endosomes, Biology, Regulated Intramembrane Proteolysis, Presenilin, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Humans, Conformation, Integral membrane protein, Gamma secretase, Presenilin 1, Transport Regulation, Subcellular localization, Presenilin 2, Amyloid beta, Presenilins, Structure, Gamma-secretase, Cell Biology, Sheddase, Alzheimer's disease, Transmembrane protein, Cell biology, Transmembrane domain, 030104 developmental biology, Familial AD, biology.protein, Amyloid Precursor Protein Secretases, APP, Lysosomes, 030217 neurology & neurosurgery, Developmental Biology

الوصف: γ-Secretase cleavage is essential for many biological processes and its dysregulation is linked to disease, including cancer and Alzheimer's disease. Therefore, understanding the regulation of its activity is of major importance to improve drug design and develop novel therapeutics. γ-Secretase belongs to the family of intramembrane cleaving proteases (i-CLiPs), which cleaves its substrates in a process termed regulated intramembrane proteolysis (RIP). During RIP, type-I transmembrane proteins are first cleaved within their ectodomain by a sheddase and then within their transmembrane domain by γ-secretase. γ-Secretase is composed of four integral membrane proteins that are all essential for its function: presenilin (PSEN), anterior pharynx defective 1 (APH1), nicastrin (NCT) and presenilin enhancer 2 (PEN-2). Given the presence of two PSEN homologues (PSEN1 & 2) and several APH1 isoforms, a heterogeneity exists in cellular γ-secretase complexes. It is becoming clear that each of these complexes has overlapping as well as distinct biological characteristics. This review summarizes our current knowledge on complex formation, trafficking, subcellular localization, interactors and the structure of γ-secretase, with a focus, when possible or known, on the contribution of PSEN1 and PSEN2 herein. ispartof: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY vol:105 pages:12-26 ispartof: location:England status: published

وصف الملف: Print-Electronic

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e43c8b4928ba7886b518f061969384f5Test
https://pubmed.ncbi.nlm.nih.gov/32146031Test