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2003 Fiscal Year Final Research Report Summary

Development of a high-pressure treatment for amyloidosis

Research Project

Project/Area Number 13558082
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Structural biochemistry
Research InstitutionKobe University

Principal Investigator

TACHIBANA Hideki  Kobe Univ., Fac.Sci., Dept.Biol., Assoc.Prof., 理学部, 助教授 (70126118)

Co-Investigator(Kenkyū-buntansha) KUWATA Kazuo  Gifu Univ., Sch.Med., Dept.Biochem.Biophys., Assoc.Prof., 医学部, 助教授 (00170142)
Project Period (FY) 2001 – 2003
Keywordslysozyme / amyloid / high-pressure NMR / prion / metastable intermediate
Research Abstract

1. A disulfide-deficient variant of hen lysozyme self-associates into a 17-S assemblage that contains intermolecular beta-structure. Upon prolonged incubation over weeks to months, amyloid-like fibrils are spontaneously formed. No specific, partially unfolded conformer is involved, and fibrils are formed starting from an intrinsically unfolded monomeric state and passing through a precursor with a spontaneous build-up of intermolecular beta-structure.
2. The 17-S precursor reversibly dissociates under hydrostatic pressure of several hundred to two thousand bars. It is characterized with a Gibbs energy for association of -23.3 kJ and a volume increase of 52.7 ml per mol of monomer unit, and involves interaction of hydrophobic residues in the initial association step.
3. By carrying out two-dimensional NMR measurements under variable pressure, a metastable conformer of the normal cellular isoform of prion protein (PrP^c) has been found to occur at a population of 1 %, in which helices B an … More d C are disordered. This metastable conformer is most logically PrP^* that is implicated in the step for transformation of PrP^c to the infectious prion protein (PrP^<Sc>) via interaction with a template PrP^<Sc>. On the other hand, the conformational characteristics of a fibril-forming fragment of the mouse prion protein have been investigated by using hydrogen-deuterium exchange measurements and molecular dynamics simulations. Fibril formation was shown to involve polyalanine stacking.
4. There exists a correlation for prion protein between the residue-wise stability determined by high-pressure NMR spectroscopy and slow fluctuations determined by the CPMG method at ambient pressure. This indicates that the metastable conformer revealed by high-pressure NMR can be acquired through slow conformational fluctuations under physiological conditions. Cavities exist at the site of large fluctuation, which strongly suggests that the screening for the molecules that bind to the cavity leads to the development of drugs for the treatment of prion disease or amyloidosis. Less

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Tachibana, H.: "Native-like tertiary structure formation in the α-domain of a hen lysozyme two-disulfide variant."Journal of Molecular Biology. 314. 311-320 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Noda, Y.: "NMR Structural Study of Two-disulfide Variant of Hen Lysozyme"Biochemistry. 41. 2130-2139 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 桑田 一夫: "プリオン病の構造医学"蛋白質・核酸・酵素. 47. 1292-1298 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuwata, K.: "Locally Disordered Conformer of the Hamster Prion Protein : A Crucial Intermediate to PrP^<Sc>?"Biochemistry. 41. 12277-12283 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuwata, K.: "NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126."Proc.Natl.Acad.Sci.USA. 100. 14790-14795 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Niraula, T.N.: "Pressure-dissociable reversible assembly of intrinsically denatured lysozyme is a precursor for amyloid fibrils"Proc.Natl.Acad.Sci.USA. 101. 4089-4093 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tachibana, H.: ""Disulfide-Bond Associated Protein Folding" in Encyclopedia of Nanoscience and Nanotechnology (H.S.Nalwa, Ed.)"American Scientific Publishers. 10,000(30) (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hideki, TACHIBANA: "Native-like tertiary structure formation in the α-domain of a hen lysozyme two-disulfide variant"Journal of Molecular Biology. 314. 311-320 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yasuo, NODA: "NMR Structural Study of Two-disulfide Variant of Hen Lysozyme : 2SS[6-127,30-115]-A disulfide Inermediate with a Partly Unfolded Structure"Biochemistry. 41. 2130-2139 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo, KUWATA: "Structural medicine and structure-based drug design for protein diseases (in Japanese)"Tanpakusitsu Kakusan Koso. 47. 1292-1298 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo, KUWATA: "Locally Disordered Conformer of the Hamster Prion Protein : A Crucial Intermediate to PrP^<Sc>?"Biochemistry. 41. 12277-12283 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kazuo, KUWATA: "NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126"Proc.Natl.Acad.Sci.USA. 100. 14790-14795 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tara, N.NIRAULA: "Pressure-dissociable reversible assembly of intrinsically denatured lysozyme is a precursor for amyloid fibrils"Proc.Natl.Acad.Sci.USA. 101. 4089-4093 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hideki, TACHIBANA: "Disulfide-Bond Associated Protein Folding"Encyclopedia of Nanoscience and Nanotechnology (H.S.Nalwa, Ed.) (American Scientific Publishers). 2. 443-473 (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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