Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease
The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ε-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ε-efficiency of γ-secretase cleavage and some eve...
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| description | The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ε-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ε-efficiency of γ-secretase cleavage and some even shift entry into production lines. Since cleavage occurs within the TMD, a relationship between processing and TMD structure and dynamics seems obvious. Using molecular dynamic simulations, we dissect the dynamic features of wild-type and seven FAD-mutants into local and global components. Mutations consistently enhance hydrogen-bond fluctuations upstream of the ε-cleavage sites but maintain strong helicity there. Dynamic perturbation-response scanning reveals that FAD-mutants target backbone motions utilized in the bound state. Those motions, obscured by large-scale motions in the pre-bound state, provide (i) a dynamic mechanism underlying the proposed coupling between binding and ε-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type. |
| doi_str_mv | 10.1371/journal.pone.0200077 |
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Those motions, obscured by large-scale motions in the pre-bound state, provide (i) a dynamic mechanism underlying the proposed coupling between binding and ε-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0200077</identifier><identifier>PMID: 29966005</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer's disease ; Amyloid precursor protein ; Biology and Life Sciences ; Cleavage ; Coupling (molecular) ; Docking ; Earth Sciences ; Efficiency ; Enzymes ; Flexibility ; Helicity ; Hydrogen ; Kinases ; Molecular chains ; Molecular structure ; Mutants ; Mutation ; Peptides ; Physical Sciences ; Physics ; Production lines ; Proteins ; Secretase ; Transmembrane domains ; Variation</subject><ispartof>PloS one, 2018-07, Vol.13 (7), p.e0200077-e0200077</ispartof><rights>2018 Götz, Scharnagl. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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ε-efficiency in familial Alzheimer's disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-07-02</date><risdate>2018</risdate><volume>13</volume><issue>7</issue><spage>e0200077</spage><epage>e0200077</epage><pages>e0200077-e0200077</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ε-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ε-efficiency of γ-secretase cleavage and some even shift entry into production lines. Since cleavage occurs within the TMD, a relationship between processing and TMD structure and dynamics seems obvious. Using molecular dynamic simulations, we dissect the dynamic features of wild-type and seven FAD-mutants into local and global components. Mutations consistently enhance hydrogen-bond fluctuations upstream of the ε-cleavage sites but maintain strong helicity there. Dynamic perturbation-response scanning reveals that FAD-mutants target backbone motions utilized in the bound state. 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| subjects | Alzheimer's disease Amyloid precursor protein Biology and Life Sciences Cleavage Coupling (molecular) Docking Earth Sciences Efficiency Enzymes Flexibility Helicity Hydrogen Kinases Molecular chains Molecular structure Mutants Mutation Peptides Physical Sciences Physics Production lines Proteins Secretase Transmembrane domains Variation |
| title | Dissecting conformational changes in APP's transmembrane domain linked to ε-efficiency in familial Alzheimer's disease |
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