| http://purl.uniprot.org/citations/23253155 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/23253155 | http://www.w3.org/2000/01/rdf-schema#comment | "The molecular mechanisms governing γ-secretase cleavage specificity are not fully understood. Herein, we demonstrate that extending the transmembrane domain of the amyloid precursor protein-derived C99 substrate in proximity to the cytosolic face strongly influences γ-secretase cleavage specificity. Sequential insertion of leucines or replacement of membrane-anchoring lysines by leucines elevated the production of Aβ42, whilst lowering production of Aβ40. A single insertion or replacement was sufficient to produce this phenotype, suggesting that the helical length distal to the ε-site is a critical determinant of γ-secretase cleavage specificity. Replacing the lysine at the luminal membrane border (K28) with glutamic acid (K28E) increased Aβ37 and reduced Aβ42 production. Maintaining a positive charge with an arginine replacement, however, did not alter cleavage specificity. Using two potent and structurally distinct γ-secretase modulators (GSMs), we elucidated the contribution of K28 to the modulatory mechanism. Surprisingly, whilst lowering the potency of the non-steroidal anti-inflammatory drug-type GSM, the K28E mutation converted a heteroaryl-type GSM to an inverse GSM. This result implies the proximal lysine is critical for the GSM mechanism and pharmacology. This region is likely a major determinant for substrate binding and we speculate that modulation of substrate binding is the fundamental mechanism by which GSMs exert their action."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.org/dc/terms/identifier | "doi:10.1111/jnc.12129"xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Vilbois F."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Beher D."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Hussain I."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Permanne B."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Losberger C."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Baguet A."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Genoud S."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Ousson S."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/author | "Saric A."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/date | "2013"xsd:gYear |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/name | "J Neurochem"xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/pages | "610-619"xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/title | "Substrate determinants in the C99 juxtamembrane domains differentially affect gamma-secretase cleavage specificity and modulator pharmacology."xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://purl.uniprot.org/core/volume | "125"xsd:string |
| http://purl.uniprot.org/citations/23253155 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/23253155 |
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| http://purl.uniprot.org/uniprot/#_A0A218KGR2-mappedCitation-23253155 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/23253155 |
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| http://purl.uniprot.org/uniprot/#_B4DGD0-mappedCitation-23253155 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/23253155 |
| http://purl.uniprot.org/uniprot/#_B3KQT0-mappedCitation-23253155 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/23253155 |