Cargando…

Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Meewhi, Bezprozvanny, Ilya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709358/
https://www.ncbi.nlm.nih.gov/pubmed/34948396
http://dx.doi.org/10.3390/ijms222413600
_version_ 1784622915394732032
author Kim, Meewhi
Bezprozvanny, Ilya
author_facet Kim, Meewhi
Bezprozvanny, Ilya
author_sort Kim, Meewhi
collection PubMed
description Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations—M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP.
format Online
Article
Text
id pubmed-8709358
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-87093582021-12-25 Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations Kim, Meewhi Bezprozvanny, Ilya Int J Mol Sci Communication Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations—M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP. MDPI 2021-12-18 /pmc/articles/PMC8709358/ /pubmed/34948396 http://dx.doi.org/10.3390/ijms222413600 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Kim, Meewhi
Bezprozvanny, Ilya
Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title_full Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title_fullStr Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title_full_unstemmed Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title_short Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations
title_sort conformational models of app processing by gamma secretase based on analysis of pathogenic mutations
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709358/
https://www.ncbi.nlm.nih.gov/pubmed/34948396
http://dx.doi.org/10.3390/ijms222413600
work_keys_str_mv AT kimmeewhi conformationalmodelsofappprocessingbygammasecretasebasedonanalysisofpathogenicmutations
AT bezprozvannyilya conformationalmodelsofappprocessingbygammasecretasebasedonanalysisofpathogenicmutations