2lp1 Citations

The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.

Abstract

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved α helix, making it well suited for processive cleavage by γ-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.

Reviews - 2lp1 mentioned but not cited (3)

  1. Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms. Mori T, Miyashita N, Im W, Feig M, Sugita Y. Biochim Biophys Acta 1858 1635-1651 (2016)
  2. Alzheimer's disease--a panorama glimpse. Zhao LN, Lu L, Chew LY, Mu Y. Int J Mol Sci 15 12631-12650 (2014)
  3. Substrate-Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype. Liu X, Zhao J, Zhang Y, Ubarretxena-Belandia I, Forth S, Lieberman RL, Wang C. Front Mol Neurosci 13 65 (2020)

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Reviews citing this publication (79)

  1. Excitotoxicity: bridge to various triggers in neurodegenerative disorders. Mehta A, Prabhakar M, Kumar P, Deshmukh R, Sharma PL. Eur J Pharmacol 698 6-18 (2013)
  2. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. van der Kant R, Goldstein LSB, Ossenkoppele R. Nat Rev Neurosci 21 21-35 (2020)
  3. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Vance JE. Dis Model Mech 5 746-755 (2012)
  4. Emerging Diversity in Lipid-Protein Interactions. Corradi V, Sejdiu BI, Mesa-Galloso H, Abdizadeh H, Noskov SY, Marrink SJ, Tieleman DP. Chem Rev 119 5775-5848 (2019)
  5. Mitochondria-associated ER membranes in Alzheimer disease. Schon EA, Area-Gomez E. Mol Cell Neurosci 55 26-36 (2013)
  6. The role of cholesterol in membrane fusion. Yang ST, Kreutzberger AJB, Lee J, Kiessling V, Tamm LK. Chem Phys Lipids 199 136-143 (2016)
  7. Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer's disease. Dawkins E, Small DH. J Neurochem 129 756-769 (2014)
  8. Cellular functions of the amyloid precursor protein from development to dementia. van der Kant R, Goldstein LS. Dev Cell 32 502-515 (2015)
  9. Pathways to Alzheimer's disease. Hardy J, Bogdanovic N, Winblad B, Portelius E, Andreasen N, Cedazo-Minguez A, Zetterberg H. J Intern Med 275 296-303 (2014)
  10. Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. Wood WG, Li L, Müller WE, Eckert GP. J Neurochem 129 559-572 (2014)
  11. Development and mechanism of γ-secretase modulators for Alzheimer's disease. Crump CJ, Johnson DS, Li YM. Biochemistry 52 3197-3216 (2013)
  12. Cholesterol as a co-solvent and a ligand for membrane proteins. Song Y, Kenworthy AK, Sanders CR. Protein Sci 23 1-22 (2014)
  13. Cholesterol and Alzheimer's Disease; From Risk Genes to Pathological Effects. Feringa FM, van der Kant R. Front Aging Neurosci 13 690372 (2021)
  14. Intracellular Cholesterol Trafficking and Impact in Neurodegeneration. Arenas F, Garcia-Ruiz C, Fernandez-Checa JC. Front Mol Neurosci 10 382 (2017)
  15. Non-covalent binding of membrane lipids to membrane proteins. Yeagle PL. Biochim Biophys Acta 1838 1548-1559 (2014)
  16. Cellular cholesterol homeostasis and Alzheimer's disease. Chang TY, Yamauchi Y, Hasan MT, Chang C. J Lipid Res 58 2239-2254 (2017)
  17. Regulation of membrane protein structure and function by their lipid nano-environment. Levental I, Lyman E. Nat Rev Mol Cell Biol 24 107-122 (2023)
  18. Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts. Fabiani C, Antollini SS. Front Cell Neurosci 13 309 (2019)
  19. Brain cholesterol metabolism, oxysterols, and dementia. Hughes TM, Rosano C, Rosano C, Evans RW, Kuller LH. J Alzheimers Dis 33 891-911 (2013)
  20. Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets. Dai L, Zou L, Meng L, Qiang G, Yan M, Zhang Z. Mol Neurobiol 58 2183-2201 (2021)
  21. Syndecan-1 in Cancer: Implications for Cell Signaling, Differentiation, and Prognostication. Szatmári T, Ötvös R, Hjerpe A, Dobra K. Dis Markers 2015 796052 (2015)
  22. Lipid rafts and neurodegeneration: structural and functional roles in physiologic aging and neurodegenerative diseases. Grassi S, Giussani P, Mauri L, Prioni S, Sonnino S, Prinetti A. J Lipid Res 61 636-654 (2020)
  23. The pleiotropic effects of omega-3 docosahexaenoic acid on the hallmarks of Alzheimer's disease. Belkouch M, Hachem M, Elgot A, Lo Van A, Picq M, Guichardant M, Lagarde M, Bernoud-Hubac N. J Nutr Biochem 38 1-11 (2016)
  24. Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease. Malnar M, Hecimovic S, Mattsson N, Zetterberg H. Neurobiol Dis 72 Pt A 37-47 (2014)
  25. The hairpin conformation of the amyloid β peptide is an important structural motif along the aggregation pathway. Abelein A, Abrahams JP, Danielsson J, Gräslund A, Jarvet J, Luo J, Tiiman A, Wärmländer SK. J Biol Inorg Chem 19 623-634 (2014)
  26. Lipid rafts in neurodegeneration and neuroprotection. Sonnino S, Aureli M, Grassi S, Mauri L, Prioni S, Prinetti A. Mol Neurobiol 50 130-148 (2014)
  27. Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics. Langosch D, Scharnagl C, Steiner H, Lemberg MK. Trends Biochem Sci 40 318-327 (2015)
  28. Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores. Arbor SC, LaFontaine M, Cumbay M. Yale J Biol Med 89 5-21 (2016)
  29. Imaging mass spectrometry in neuroscience. Hanrieder J, Phan NT, Kurczy ME, Ewing AG. ACS Chem Neurosci 4 666-679 (2013)
  30. Use of electron paramagnetic resonance to solve biochemical problems. Sahu ID, McCarrick RM, Lorigan GA. Biochemistry 52 5967-5984 (2013)
  31. Mass spectrometry imaging, an emerging technology in neuropsychopharmacology. Shariatgorji M, Svenningsson P, Andrén PE. Neuropsychopharmacology 39 34-49 (2014)
  32. Cross-talk of membrane lipids and Alzheimer-related proteins. Walter J, van Echten-Deckert G. Mol Neurodegener 8 34 (2013)
  33. Panax ginseng components and the pathogenesis of Alzheimer's disease (Review). Razgonova MP, Veselov VV, Zakharenko AM, Golokhvast KS, Nosyrev AE, Cravotto G, Tsatsakis A, Spandidos DA. Mol Med Rep 19 2975-2998 (2019)
  34. Recent Progress in Alzheimer's Disease Research, Part 1: Pathology. Hane FT, Lee BY, Leonenko Z. J Alzheimers Dis 57 1-28 (2017)
  35. Cholesterol, 24-Hydroxycholesterol, and 27-Hydroxycholesterol as Surrogate Biomarkers in Cerebrospinal Fluid in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis. Wang HL, Wang YY, Liu XG, Kuo SH, Liu N, Song QY, Wang MW. J Alzheimers Dis 51 45-55 (2016)
  36. Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Silva T, Teixeira J, Remião F, Borges F. Angew Chem Int Ed Engl 52 1110-1121 (2013)
  37. The impact of cholesterol, DHA, and sphingolipids on Alzheimer's disease. Grimm MO, Zimmer VC, Lehmann J, Grimm HS, Hartmann T. Biomed Res Int 2013 814390 (2013)
  38. The role of cholesterol metabolism in Alzheimer's disease. Sun JH, Yu JT, Tan L. Mol Neurobiol 51 947-965 (2015)
  39. β-Amyloid aggregation and heterogeneous nucleation. Srivastava AK, Pittman JM, Zerweck J, Venkata BS, Moore PC, Sachleben JR, Meredith SC. Protein Sci 28 1567-1581 (2019)
  40. Cholesterol and Alzheimer's disease: a still poorly understood correlation. Ricciarelli R, Canepa E, Marengo B, Marinari UM, Poli G, Pronzato MA, Domenicotti C. IUBMB Life 64 931-935 (2012)
  41. Site-Directed Spin Labeling EPR for Studying Membrane Proteins. Sahu ID, Lorigan GA. Biomed Res Int 2018 3248289 (2018)
  42. Understanding single-pass transmembrane receptor signaling from a structural viewpoint-what are we missing? Bugge K, Lindorff-Larsen K, Kragelund BB. FEBS J 283 4424-4451 (2016)
  43. Cellular membrane fluidity in amyloid precursor protein processing. Yang X, Sun GY, Eckert GP, Lee JC. Mol Neurobiol 50 119-129 (2014)
  44. Regulation of KCNQ/Kv7 family voltage-gated K+ channels by lipids. Taylor KC, Sanders CR. Biochim Biophys Acta Biomembr 1859 586-597 (2017)
  45. Dynamic nuclear polarization methods in solids and solutions to explore membrane proteins and membrane systems. Cheng CY, Han S. Annu Rev Phys Chem 64 507-532 (2013)
  46. Solid-state NMR spectroscopy to study protein-lipid interactions. Huster D. Biochim Biophys Acta 1841 1146-1160 (2014)
  47. Domain structure and function of matrix metalloprotease 23 (MMP23): role in potassium channel trafficking. Galea CA, Nguyen HM, George Chandy K, Smith BJ, Norton RS. Cell Mol Life Sci 71 1191-1210 (2014)
  48. Metals and cholesterol: two sides of the same coin in Alzheimer's disease pathology. Wong BX, Hung YH, Bush AI, Duce JA. Front Aging Neurosci 6 91 (2014)
  49. Structure and functions of syndecans in vertebrates. Leonova EI, Galzitskaya OV. Biochemistry (Mosc) 78 1071-1085 (2013)
  50. Alzheimer's Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α. Sáez-Orellana F, Octave JN, Pierrot N. Cells 9 E1215 (2020)
  51. The quiet renaissance of protein nuclear magnetic resonance. Barrett PJ, Chen J, Cho MK, Kim JH, Lu Z, Mathew S, Peng D, Song Y, Van Horn WD, Zhuang T, Sönnichsen FD, Sanders CR. Biochemistry 52 1303-1320 (2013)
  52. Common structural features of cholesterol binding sites in crystallized soluble proteins. Bukiya AN, Dopico AM. J Lipid Res 58 1044-1054 (2017)
  53. Why cells need intramembrane proteases - a mechanistic perspective. Strisovsky K. FEBS J 283 1837-1845 (2016)
  54. Challenges and approaches to understand cholesterol-binding impact on membrane protein function: an NMR view. Jaipuria G, Ukmar-Godec T, Zweckstetter M. Cell Mol Life Sci 75 2137-2151 (2018)
  55. Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer's disease. Rudajev V, Novotny J. Front Mol Neurosci 15 937056 (2022)
  56. Electron Paramagnetic Resonance as a Tool for Studying Membrane Proteins. Sahu ID, Lorigan GA. Biomolecules 10 E763 (2020)
  57. Rational heterodoxy: cholesterol reformation of the amyloid doctrine. Castello MA, Soriano S. Ageing Res Rev 12 282-288 (2013)
  58. Physiological functions of SPP/SPPL intramembrane proteases. Mentrup T, Cabrera-Cabrera F, Fluhrer R, Schröder B. Cell Mol Life Sci 77 2959-2979 (2020)
  59. Amyloid precursor protein (APP) and amyloid β (Aβ) interact with cell adhesion molecules: Implications in Alzheimer's disease and normal physiology. Pfundstein G, Nikonenko AG, Sytnyk V. Front Cell Dev Biol 10 969547 (2022)
  60. Nanoliposomes as a Therapeutic Tool for Alzheimer's Disease. Ordóñez-Gutiérrez L, Wandosell F. Front Synaptic Neurosci 12 20 (2020)
  61. 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)
  62. The membrane protein KCNQ1 potassium ion channel: Functional diversity and current structural insights. Dixit G, Dabney-Smith C, Lorigan GA. Biochim Biophys Acta Biomembr 1862 183148 (2020)
  63. 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 2897 (2021)
  64. Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation. Bécot A, Volgers C, van Niel G. Biomedicines 8 E272 (2020)
  65. Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer's disease. Kulas JA, Weigel TK, Ferris HA. Drug Dev Res 81 194-205 (2020)
  66. Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders. Roussotte FF, Daianu M, Jahanshad N, Leonardo CD, Thompson PM. Brain Imaging Behav 8 217-233 (2014)
  67. New findings concerning vertebrate porin II--on the relevance of glycine motifs of type-1 VDAC. Thinnes FP. Mol Genet Metab 108 212-224 (2013)
  68. Role of Cholesterol and Phospholipids in Amylin Misfolding, Aggregation and Etiology of Islet Amyloidosis. Singh S, Trikha S, Bhowmick DC, Sarkar AA, Jeremic AM. Adv Exp Med Biol 855 95-116 (2015)
  69. Solution NMR of SNAREs, complexin and α-synuclein in association with membrane-mimetics. Liang B, Tamm LK. Prog Nucl Magn Reson Spectrosc 105 41-53 (2018)
  70. Targeting syndecan-1: new opportunities in cancer therapy. Yang Z, Chen S, Ying H, Yao W. Am J Physiol Cell Physiol 323 C29-C45 (2022)
  71. Membrane Aging as the Real Culprit of Alzheimer's Disease: Modification of a Hypothesis. Yu Q, Zhong C. Neurosci Bull 34 369-381 (2018)
  72. Role of Mitochondrial Protein Import in Age-Related Neurodegenerative and Cardiovascular Diseases. Bogorodskiy A, Okhrimenko I, Burkatovskii D, Jakobs P, Maslov I, Gordeliy V, Dencher NA, Gensch T, Voos W, Altschmied J, Haendeler J, Borshchevskiy V. Cells 10 3528 (2021)
  73. Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer's Disease? Di Natale G, Sabatino G, Sciacca MFM, Tosto R, Milardi D, Pappalardo G. Molecules 27 5066 (2022)
  74. Endosomal trafficking and related genetic underpinnings as a hub in Alzheimer's disease. Limone A, Veneruso I, D'Argenio V, Sarnataro D. J Cell Physiol 237 3803-3815 (2022)
  75. Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates. Papadopoulos N, Suelves N, Perrin F, Vadukul DM, Vrancx C, Constantinescu SN, Kienlen-Campard P. Biomedicines 10 2753 (2022)
  76. The Pursuit of the "Inside" of the Amyloid Hypothesis-Is C99 a Promising Therapeutic Target for Alzheimer's Disease? Takasugi N, Komai M, Kaneshiro N, Ikeda A, Kamikubo Y, Uehara T. Cells 12 454 (2023)
  77. Sulfotransferase 2B1b, Sterol Sulfonation, and Disease. Cook I, Leyh TS. Pharmacol Rev 75 521-531 (2023)
  78. Utilizing magnetic resonance techniques to study membrane interactions of amyloid peptides. Rajput S, Sani MA, Keizer DW, Separovic F. Biochem Soc Trans 49 1457-1465 (2021)
  79. Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol. Rudajev V, Novotny J. Cell Biosci 13 171 (2023)

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