Tracing the GSAP–APP C-99 Interaction Site in the β-Amyloid Pathway Leading to Alzheimer’s Disease

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  • Authors:
  • Deekshi Angira
  • Rupesh Chikhale
  • Kapilkumar Mehta
  • Richard A. Bryce
  • Vijay Thiruvenkatam

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 (712IATVIVITLVMLKKQ727 (712IQ727), 719TLVMLKKKQYTSIHHGVVEVDAAVT743 (719TT743) 734GVVEVDAAVTPEERHLSKMQQNGY757 (734GY757), and 746ERHLSKMQQNGYENPTYKFFEQMQN770 (746EN770)). The results emphasize the selective interaction of peptide (719TT743) with MBP-GSAP with a dissociation constant of 0.136 μM. Further, computational modeling of the GSAP–719TT743 complex finds an optimal bound pose of 719TT743 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.

Bibliographical metadata

Original languageEnglish
Pages (from-to)3868-3879
JournalACS Chemical Neuroscience
Volume10
Issue number8
Early online date12 Jul 2019
DOIs
Publication statusPublished - 21 Aug 2019