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Tracing the GSAP-APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer's Disease. | LitMetric

AI Article Synopsis

Article Abstract

Gamma secretase activating protein (GSAP) present in β-amyloid pathway orchestrates the formation of β-amyloid plaques by γ-secretase activation and is an emerging therapeutic target for the treatment of Alzheimer's disease. It forms a ternary complex with γ-secretase and APP C-99. However, there are limited reports for the interaction of APP C-99 with GSAP. Here, we report the characterization of purified maltose binding protein (MBP) tagged human GSAP and its interaction with synthetic APP C-99 peptide fragments (IATVIVITLVMLKKQ (IQ), TLVMLKKKQYTSIHHGVVEVDAAVT (TT) GVVEVDAAVTPEERHLSKMQQNGY (GY), and ERHLSKMQQNGYENPTYKFFEQMQN (EN)). The results emphasize the selective interaction of peptide (TT) with MBP-GSAP with a dissociation constant of 0.136 μM. Further, computational modeling of the GSAP-TT complex finds an optimal bound pose of TT within an extended groove on the surface of GSAP. The preliminary results highlight the interaction between the two major proteins in the plausible ternary complex: APP C-99-GSAP-γ-secretase. It paves a futuristic path to investigate the GSAP-APP C-99 binding in detail and accentuates the role of GSAP in the β-amyloid pathway.

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Source
http://dx.doi.org/10.1021/acschemneuro.9b00332DOI Listing

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