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The E2 domains of APP and APLP1 share a conserved mode of dimerization.

Lee S, Xue Y, Hu J, Wang Y, Liu X, Demeler B, Ha Y
Biochemistry 50 5453-64 (2011)
Cited: 27 times
EuropePMC logo PMID: 21574595

Abstract

Amyloid precursor protein (APP) is genetically linked to Alzheimer's disease. APP is a type I membrane protein, and its oligomeric structure is potentially important because this property may play a role in its function or affect the processing of the precursor by the secretases to generate amyloid β-peptide. Several independent studies have shown that APP can form dimers in the cell, but how it dimerizes remains controversial. At least three regions of the precursor, including a centrally located and conserved domain called E2, have been proposed to contribute to dimerization. Here we report two new crystal structures of E2, one from APP and the other from APLP1, a mammalian APP homologue. Comparison with an earlier APP structure, which was determined in a different space group, shows that the E2 domains share a conserved and antiparallel mode of dimerization. Biophysical measurements in solution show that heparin binding induces E2 dimerization. The 2.1 Å resolution electron density map also reveals phosphate ions that are bound to the protein surface. Mutational analysis shows that protein residues interacting with the phosphate ions are also involved in heparin binding. The locations of two of these residues, Arg-369 and His-433, at the dimeric interface suggest a mechanism for heparin-induced protein dimerization.

Articles - 3pmr mentioned but not cited (6)

  1. The E2 domains of APP and APLP1 share a conserved mode of dimerization. Lee S, Xue Y, Hu J, Wang Y, Liu X, Demeler B, Ha Y. Biochemistry 50 5453-5464 (2011)
  2. Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes. Dahms SO, Mayer MC, Roeser D, Multhaup G, Than ME. Acta Crystallogr D Biol Crystallogr 71 494-504 (2015)
  3. Ultraprocessed foods and cardiovascular health: it's not just about the nutrients. Lawrence M. Am J Clin Nutr 113 257-258 (2021)
  4. In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer's Disease: Prospects for Designing New Therapeutics Compound. Shah-Abadi ME, Ariaei A, Moradi F, Rustamzadeh A, Tanha RR, Sadigh N, Marzban M, Heydari M, Ferdousie VT. Neurotox Res 41 408-430 (2023)
  5. Insights from molecular network analysis to docking of sterubin with potential targets. Viswanathan S, Subramanian K, Ramesh V, Vasanthi AHR. Bioinformation 19 1184-1192 (2023)
  6. Tianma Formula Alleviates Dementia via ACER2-Mediated Sphingolipid Signaling Pathway Involving Aβ. Lin H, Wu S, Weng Z, Wang H, Shi R, Tian M, Wang Y, He H, Wang Y, Liu X, Jian Z, Wei F, Wang P, Zhang L, Liu Y, Guo Q, Chen C, Yang W. Evid Based Complement Alternat Med 2021 6029237 (2021)


Reviews citing this publication (7)

  1. Demystifying heparan sulfate-protein interactions. Xu D, Esko JD. Annu Rev Biochem 83 129-157 (2014)
  2. Functions of Aβ, sAPPα and sAPPβ : similarities and differences. Chasseigneaux S, Allinquant B. J Neurochem 120 Suppl 1 99-108 (2012)
  3. Platelets and Alzheimer's disease: Potential of APP as a biomarker. Evin G, Li QX. World J Psychiatry 2 102-113 (2012)
  4. Structure and Synaptic Function of Metal Binding to the Amyloid Precursor Protein and its Proteolytic Fragments. Wild K, August A, Pietrzik CU, Kins S. Front Mol Neurosci 10 21 (2017)
  5. Alzheimer's disease--a panorama glimpse. Zhao LN, Lu L, Chew LY, Mu Y. Int J Mol Sci 15 12631-12650 (2014)
  6. 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)
  7. 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)

Articles citing this publication (14)

  1. Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein. Song Y, Hustedt EJ, Brandon S, Sanders CR. Biochemistry 52 5051-5064 (2013)
  2. Amyloid precursor protein dimerization and synaptogenic function depend on copper binding to the growth factor-like domain. Baumkötter F, Schmidt N, Vargas C, Schilling S, Weber R, Wagner K, Fiedler S, Klug W, Radzimanowski J, Nickolaus S, Keller S, Eggert S, Wild K, Kins S. J Neurosci 34 11159-11172 (2014)
  3. Metal binding dictates conformation and function of the amyloid precursor protein (APP) E2 domain. Dahms SO, Könnig I, Roeser D, Gührs KH, Mayer MC, Kaden D, Multhaup G, Than ME. J Mol Biol 416 438-452 (2012)
  4. sAβPPα is a Potent Endogenous Inhibitor of BACE1. Peters-Libeu C, Campagna J, Mitsumori M, Poksay KS, Spilman P, Sabogal A, Bredesen DE, John V. J Alzheimers Dis 47 545-555 (2015)
  5. Analysis of the overall structure of the multi-domain amyloid precursor protein (APP). Coburger I, Dahms SO, Roeser D, Gührs KH, Hortschansky P, Than ME. PLoS One 8 e81926 (2013)
  6. Crystal structure of amyloid precursor-like protein 1 and heparin complex suggests a dual role of heparin in E2 dimerization. Xue Y, Lee S, Ha Y. Proc Natl Acad Sci U S A 108 16229-16234 (2011)
  7. The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Xu K, Olsen O, Tzvetkova-Robev D, Tessier-Lavigne M, Nikolov DB. Genes Dev 29 785-790 (2015)
  8. Heparin induced dimerization of APP is primarily mediated by E1 and regulated by its acidic domain. Hoefgen S, Coburger I, Roeser D, Schaub Y, Dahms SO, Than ME. J Struct Biol 187 30-37 (2014)
  9. Peptide binding by catalytic domains of the protein disulfide isomerase-related protein ERp46. Funkner A, Parthier C, Schutkowski M, Zerweck J, Lilie H, Gyrych N, Fischer G, Stubbs MT, Ferrari DM. J Mol Biol 425 1340-1362 (2013)
  10. Aggregate Interactome Based on Protein Cross-linking Interfaces Predicts Drug Targets to Limit Aggregation in Neurodegenerative Diseases. Balasubramaniam M, Ayyadevara S, Ganne A, Kakraba S, Penthala NR, Du X, Crooks PA, Griffin ST, Shmookler Reis RJ. iScience 20 248-264 (2019)
  11. Novel zinc-binding site in the E2 domain regulates amyloid precursor-like protein 1 (APLP1) oligomerization. Mayer MC, Kaden D, Schauenburg L, Hancock MA, Voigt P, Roeser D, Barucker C, Than ME, Schaefer M, Multhaup G. J Biol Chem 289 19019-19030 (2014)
  12. Crystal structure of the E2 domain of amyloid precursor protein-like protein 1 in complex with sucrose octasulfate. Xue Y, Lee S, Wang Y, Ha Y. J Biol Chem 286 29748-29757 (2011)
  13. Peptides of presenilin-1 bind the amyloid precursor protein ectodomain and offer a novel and specific therapeutic approach to reduce ß-amyloid in Alzheimer's disease. Dewji NN, Singer SJ, Masliah E, Rockenstein E, Kim M, Harber M, Horwood T. PLoS One 10 e0122451 (2015)
  14. Double Mutations in a Patient with Early-Onset Alzheimer's Disease in Korea: An APP Val551Met and a PSEN2 His169Asn. Bae H, Shim KH, Yoo J, Yang YS, An SSA, Kang MJ. Int J Mol Sci 24 7446 (2023)


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