3dxe Citations

Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2.

EMBO Rep 9 1134-40 (2008)
Related entries: 3dxc, 3dxd

Cited: 56 times
EuropePMC logo PMID: 18833287

Abstract

Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (Abeta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and Abeta generation. We determined the crystal structure of the AICD in complex with the C-terminal phosphotyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T(668), an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T(668) phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.

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  1. Alzheimer's disease--a panorama glimpse. Zhao LN, Lu L, Chew LY, Mu Y. Int J Mol Sci 15 12631-12650 (2014)

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Reviews citing this publication (11)

  1. Physiological functions of APP family proteins. Müller UC, Zheng H. Cold Spring Harb Perspect Med 2 a006288 (2012)
  2. Amyloid precursor protein and its homologues: a family of proteolysis-dependent receptors. Jacobsen KT, Iverfeldt K. Cell Mol Life Sci 66 2299-2318 (2009)
  3. Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? Beel AJ, Sakakura M, Barrett PJ, Sanders CR. Biochim Biophys Acta 1801 975-982 (2010)
  4. Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease. Bukhari H, Glotzbach A, Kolbe K, Leonhardt G, Loosse C, Müller T. Prog Neurobiol 156 189-213 (2017)
  5. The Role of APP in Structural Spine Plasticity. Montagna E, Dorostkar MM, Herms J. Front Mol Neurosci 10 136 (2017)
  6. Survey of the year 2008: applications of isothermal titration calorimetry. Falconer RJ, Penkova A, Jelesarov I, Collins BM. J Mol Recognit 23 395-413 (2010)
  7. Regulation of the alternative β-secretase meprin β by ADAM-mediated shedding. Scharfenberg F, Armbrust F, Marengo L, Pietrzik C, Becker-Pauly C. Cell Mol Life Sci 76 3193-3206 (2019)
  8. APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins. Guénette S, Strecker P, Kins S. Front Mol Neurosci 10 87 (2017)
  9. Amyloidogenesis: What Do We Know So Far? Alraawi Z, Banerjee N, Mohanty S, Kumar TKS. Int J Mol Sci 23 13970 (2022)
  10. Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer's Disease Development. Urban AS, Pavlov KV, Kamynina AV, Okhrimenko IS, Arseniev AS, Bocharov EV. Molecules 26 (2021)
  11. Structural biology of cell surface receptors implicated in Alzheimer's disease. Hermans SJ, Nero TL, Morton CJ, Gooi JH, Crespi GAN, Hancock NC, Gao C, Ishii K, Markulić J, Parker MW. Biophys Rev 14 233-255 (2022)

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