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Probing the N-terminal β-sheet conversion in the crystal structure of the human prion protein bound to a nanobody.

Abskharon RN, Giachin G, Wohlkonig A, Soror SH, Pardon E, Legname G, Steyaert J
J Am Chem Soc 136 937-44 (2014)
Cited: 55 times
EuropePMC logo PMID: 24400836

Abstract

Prions are fatal neurodegenerative transmissible agents causing several incurable illnesses in humans and animals. Prion diseases are caused by the structural conversion of the cellular prion protein, PrP(C), into its misfolded oligomeric form, known as prion or PrP(Sc). The canonical human PrP(C) (HuPrP) fold features an unstructured N-terminal part (residues 23-124) and a well-defined C-terminal globular domain (residues 125-231). Compelling evidence indicates that an evolutionary N-terminal conserved motif AGAAAAGA (residues 113-120) plays an important role in the conversion to PrP(Sc). The intrinsic flexibility of the N-terminal has hampered efforts to obtain detailed atomic information on the structural features of this palindromic region. In this study, we crystallized the full-length HuPrP in complex with a nanobody (Nb484) that inhibits prion propagation. In the complex, the prion protein is unstructured from residue 23 to 116. The palindromic motif adopts a stable and fully extended configuration to form a three-stranded antiparallel β-sheet with the β1 and β2 strands, demonstrating that the full-length HuPrP(C) can adopt a more elaborate β0-β1-α1-β2-α2-α3 structural organization than the canonical β1-α1-β2-α2-α3 prion-like fold. From this structure, it appears that the palindromic motif mediates β-enrichment in the PrP(C) monomer as one of the early events in the conversion of PrP(C) into PrP(Sc).

Articles - 4n9o mentioned but not cited (2)

  1. Met/Val129 polymorphism of the full-length human prion protein dictates distinct pathways of amyloid formation. Pauly T, Bolakhrif N, Kaiser J, Nagel-Steger L, Gremer L, Gohlke H, Willbold D. J Biol Chem 298 102430 (2022)
  2. Recognition Mechanisms between a Nanobody and Disordered Epitopes of the Human Prion Protein: An Integrative Molecular Dynamics Study. Mollica L, Mollica L, Giachin G. J Chem Inf Model 63 531-545 (2023)


Reviews citing this publication (25)

  1. Nanobody-based products as research and diagnostic tools. De Meyer T, Muyldermans S, Depicker A. Trends Biotechnol 32 263-270 (2014)
  2. Nanobodies and recombinant binders in cell biology. Helma J, Cardoso MC, Muyldermans S, Leonhardt H. J Cell Biol 209 633-644 (2015)
  3. Nanobodies to Study G Protein-Coupled Receptor Structure and Function. Manglik A, Kobilka BK, Steyaert J. Annu Rev Pharmacol Toxicol 57 19-37 (2017)
  4. Camelid nanobodies: killing two birds with one stone. Desmyter A, Spinelli S, Roussel A, Cambillau C. Curr Opin Struct Biol 32 1-8 (2015)
  5. Nanobodies as Probes for Protein Dynamics in Vitro and in Cells. Dmitriev OY, Lutsenko S, Muyldermans S. J Biol Chem 291 3767-3775 (2016)
  6. Exploring cellular biochemistry with nanobodies. Cheloha RW, Harmand TJ, Wijne C, Schwartz TU, Ploegh HL. J Biol Chem 295 15307-15327 (2020)
  7. Small molecule probes of protein aggregation. Young LM, Ashcroft AE, Radford SE. Curr Opin Chem Biol 39 90-99 (2017)
  8. Structural Consequences of Copper Binding to the Prion Protein. Salzano G, Giachin G, Legname G. Cells 8 E770 (2019)
  9. Elucidating the function of the prion protein. Legname G. PLoS Pathog 13 e1006458 (2017)
  10. Single-Domain Antibodies as Therapeutic and Imaging Agents for the Treatment of CNS Diseases. Bélanger K, Iqbal U, Tanha J, MacKenzie R, Moreno M, Stanimirovic D. Antibodies (Basel) 8 E27 (2019)
  11. Transition of the prion protein from a structured cellular form (PrPC ) to the infectious scrapie agent (PrPSc ). Baral PK, Yin J, Aguzzi A, James MNG. Protein Sci 28 2055-2063 (2019)
  12. Conformational selection in amyloid-based immunotherapy: Survey of crystal structures of antibody-amyloid complexes. Ma B, Zhao J, Nussinov R. Biochim Biophys Acta 1860 2672-2681 (2016)
  13. Transportation of Single-Domain Antibodies through the Blood-Brain Barrier. Ruiz-López E, Schuhmacher AJ. Biomolecules 11 1131 (2021)
  14. Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance. Loh D, Reiter RJ. Molecules 27 705 (2022)
  15. Synthetic prions and other human neurodegenerative proteinopathies. Le NT, Narkiewicz J, Aulić S, Salzano G, Tran HT, Scaini D, Moda F, Giachin G, Legname G. Virus Res 207 25-37 (2015)
  16. Immunotherapy against Prion Disease. Ma Y, Ma J. Pathogens 9 E216 (2020)
  17. On the role of the cellular prion protein in the uptake and signaling of pathological aggregates in neurodegenerative diseases. Legname G, Scialò C. Prion 14 257-270 (2020)
  18. Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography. Ruiz-López E, Calatayud-Pérez J, Castells-Yus I, Gimeno-Peribáñez MJ, Mendoza-Calvo N, Morcillo MÁ, Schuhmacher AJ. Cancers (Basel) 14 74 (2021)
  19. Prion protein-specific antibodies-development, modes of action and therapeutics application. Rovis TL, Legname G. Viruses 6 3719-3737 (2014)
  20. Engineered Extracellular Vesicles/Exosomes as a New Tool against Neurodegenerative Diseases. Ferrantelli F, Chiozzini C, Leone P, Manfredi F, Federico M. Pharmaceutics 12 E529 (2020)
  21. Roles, Characteristics, and Analysis of Intrinsically Disordered Proteins: A Minireview. Lermyte F. Life (Basel) 10 E320 (2020)
  22. Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases. Yoon S, Go G, Yoon Y, Lim J, Lee G, Lee S. Biomolecules 11 784 (2021)
  23. Antibodies: From novel repertoires to defining and refining the structure of biologically important targets. Conroy PJ, Law RH, Caradoc-Davies TT, Whisstock JC. Methods 116 12-22 (2017)
  24. Applications of nanobodies in brain diseases. Zheng F, Pang Y, Li L, Pang Y, Zhang J, Wang X, Raes G. Front Immunol 13 978513 (2022)
  25. Copper coordination modulates prion conversion and infectivity in mammalian prion proteins. Legname G. Prion 17 1-6 (2023)

Articles citing this publication (28)

  1. Liquid and Hydrogel Phases of PrPC Linked to Conformation Shifts and Triggered by Alzheimer's Amyloid-β Oligomers. Kostylev MA, Tuttle MD, Lee S, Klein LE, Takahashi H, Cox TO, Gunther EC, Zilm KW, Strittmatter SM. Mol Cell 72 426-443.e12 (2018)
  2. Acid-induced molten globule state of a prion protein: crucial role of Strand 1-Helix 1-Strand 2 segment. Honda RP, Yamaguchi KI, Kuwata K. J Biol Chem 289 30355-30363 (2014)
  3. The non-octarepeat copper binding site of the prion protein is a key regulator of prion conversion. Giachin G, Mai PT, Tran TH, Salzano G, Benetti F, Migliorati V, Arcovito A, Della Longa S, Mancini G, D'Angelo P, Legname G. Sci Rep 5 15253 (2015)
  4. Supramolecular Glycosylation Accelerates Proteolytic Degradation of Peptide Nanofibrils. Yuan D, Shi J, Du X, Zhou N, Xu B. J Am Chem Soc 137 10092-10095 (2015)
  5. Structural evidence for the critical role of the prion protein hydrophobic region in forming an infectious prion. Abskharon R, Wang F, Wohlkonig A, Ruan J, Soror S, Giachin G, Pardon E, Zou W, Legname G, Ma J, Steyaert J. PLoS Pathog 15 e1008139 (2019)
  6. Structural basis for the complete resistance of the human prion protein mutant G127V to prion disease. Zheng Z, Zhang M, Wang Y, Ma R, Guo C, Feng L, Wu J, Yao H, Lin D. Sci Rep 8 13211 (2018)
  7. Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease. Abskharon R, Seidler PM, Sawaya MR, Cascio D, Yang TP, Philipp S, Williams CK, Newell KL, Ghetti B, DeTure MA, Dickson DW, Vinters HV, Felgner PL, Nakajima R, Glabe CG, Eisenberg DS. J Biol Chem 295 10662-10676 (2020)
  8. Pathogenic Mutations within the Disordered Palindromic Region of the Prion Protein Induce Structure Therein and Accelerate the Formation of Misfolded Oligomers. Sabareesan AT, Udgaonkar JB. J Mol Biol 428 3935-3947 (2016)
  9. A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles. Mercer RCC, Daude N, Dorosh L, Fu ZL, Mays CE, Gapeshina H, Wohlgemuth SL, Acevedo-Morantes CY, Yang J, Cashman NR, Coulthart MB, Pearson DM, Joseph JT, Wille H, Safar JG, Jansen GH, Stepanova M, Sykes BD, Westaway D. PLoS Pathog 14 e1006826 (2018)
  10. Research Support, Non-U.S. Gov't Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment. Wang J, Kang G, Yuan H, Cao X, Huang H, de Marco A. Front Immunol 12 838082 (2021)
  11. Development and structural determination of an anti-PrPC aptamer that blocks pathological conformational conversion of prion protein. Mashima T, Lee JH, Kamatari YO, Hayashi T, Nagata T, Nishikawa F, Nishikawa S, Kinoshita M, Kuwata K, Katahira M. Sci Rep 10 4934 (2020)
  12. Mechanism of misfolding of the human prion protein revealed by a pathological mutation. Sanz-Hernández M, Barritt JD, Sobek J, Hornemann S, Aguzzi A, De Simone A. Proc Natl Acad Sci U S A 118 e2019631118 (2021)
  13. Simulations of membrane-bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding. Cheng CJ, Koldsø H, Van der Kamp MW, Schiøtt B, Daggett V. J Neurochem 142 171-182 (2017)
  14. Direct interaction of DNMT inhibitors to PrPC suppresses pathogenic process of prion. Kim DH, Ren C, Ryou C, Li J. Acta Pharm Sin B 9 952-959 (2019)
  15. Effects of the A117V mutation on the folding and aggregation of palindromic sequences (PrP113-120) in prion: insights from replica exchange molecular dynamics simulations. Ning L, Wang Q, Zheng Y, Liu H, Yao X. Mol Biosyst 11 647-655 (2015)
  16. Structural transitions in full-length human prion protein detected by xenon as probe and spin labeling of the N-terminal domain. Narayanan SP, Nair DG, Schaal D, Barbosa de Aguiar M, Wenzel S, Kremer W, Schwarzinger S, Kalbitzer HR. Sci Rep 6 28419 (2016)
  17. Functional and Biochemical Characterization of Alvinella pompejana Cys-Loop Receptor Homologues. Wijckmans E, Nys M, Debaveye S, Brams M, Pardon E, Willegems K, Bertrand D, Steyaert J, Efremov R, Ulens C. PLoS One 11 e0151183 (2016)
  18. Nanobodies targeting ABCC3 for immunotargeted applications in glioblastoma. Ruiz-López E, Jovčevska I, González-Gómez R, Tejero H, Al-Shahrour F, Muyldermans S, Schuhmacher AJ. Sci Rep 12 22581 (2022)
  19. Novel quaternary structures of the human prion protein globular domain. Bortot LO, Rangel VL, Pavlovici FA, El Omari K, Wagner A, Brandao-Neto J, Talon R, von Delft F, Reidenbach AG, Vallabh SM, Minikel EV, Schreiber S, Nonato MC. Biochimie 191 118-125 (2021)
  20. Polymorphisms at amino acid residues 141 and 154 influence conformational variation in ovine PrP. Yang S, Thackray AM, Hopkins L, Monie TP, Burke DF, Bujdoso R. Biomed Res Int 2014 372491 (2014)
  21. The protean prion protein. Requena JR. PLoS Biol 18 e3000754 (2020)
  22. Soluble polymorphic bank vole prion proteins induced by co-expression of quiescin sulfhydryl oxidase in E. coli and their aggregation behaviors. Abskharon R, Dang J, Elfarash A, Wang Z, Shen P, Zou LS, Hassan S, Wang F, Fujioka H, Steyaert J, Mulaj M, Surewicz WK, Castilla J, Wohlkonig A, Zou WQ. Microb Cell Fact 16 170 (2017)
  23. Structural effects of the highly protective V127 polymorphism on human prion protein. Hosszu LLP, Conners R, Sangar D, Batchelor M, Sawyer EB, Fisher S, Cliff MJ, Hounslow AM, McAuley K, Leo Brady R, Jackson GS, Bieschke J, Waltho JP, Collinge J. Commun Biol 3 402 (2020)
  24. Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils. Abskharon R, Pan H, Sawaya MR, Seidler PM, Olivares EJ, Chen Y, Murray KA, Zhang J, Lantz C, Bentzel M, Boyer DR, Cascio D, Nguyen BA, Hou K, Cheng X, Pardon E, Williams CK, Nana AL, Vinters HV, Spina S, Grinberg LT, Seeley WW, Steyaert J, Glabe CG, Ogorzalek Loo RR, Loo JA, Eisenberg DS. Proc Natl Acad Sci U S A 120 e2300258120 (2023)
  25. A general approach for stabilizing nanobodies for intracellular expression. Dingus JG, Tang JCY, Amamoto R, Wallick GK, Cepko CL. Elife 11 e68253 (2022)
  26. Binding modes of potential anti-prion phytochemicals to PrPC structures in silico. Neupane S, Khadka J, Rayamajhi S, Pandey AS. J Ayurveda Integr Med 14 100750 (2023)
  27. Early Stages of RNA-Mediated Conversion of Human Prions. Lubecka EA, Hansmann UHE. J Phys Chem B 126 6221-6230 (2022)
  28. Structural and dynamical determinants of a β-sheet-enriched intermediate involved in amyloid fibrillar assembly of human prion protein. Russo L, Salzano G, Corvino A, Bistaffa E, Moda F, Celauro L, D'Abrosca G, Isernia C, Milardi D, Giachin G, Malgieri G, Legname G, Fattorusso R. Chem Sci 13 10406-10427 (2022)


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