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Functional amyloid formation within mammalian tissue

Academic Article
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Overview

related to degree

  • Fowler, Douglas, Ph.D. in Chemistry, Scripps Research 2002 - 2007

authors

  • Fowler, Douglas
  • Koulov, A. V.
  • Alory-Jost, C.
  • Marks, M. S.
  • Balch, William E.
  • Kelly, Jeffery

publication date

  • 2006

journal

  • PLoS Biology  Journal

abstract

  • Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

subject areas

  • Amyloid
  • Animals
  • Cattle
  • Congo Red
  • Eye
  • Melanins
  • Melanosomes
  • Membrane Glycoproteins
  • Microscopy, Electron
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Peptide Fragments
  • Protein Folding
  • Proteins
  • Recombinant Proteins
  • Spectroscopy, Fourier Transform Infrared
  • Staining and Labeling
  • Thiazoles
  • X-Ray Diffraction
  • gp100 Melanoma Antigen
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Identity

PubMed Central ID

  • PMC1288039

International Standard Serial Number (ISSN)

  • 1544-9173

Digital Object Identifier (DOI)

  • 10.1371/journal.pbio.0040006

PubMed ID

  • 16300414
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Additional Document Info

start page

  • 100

end page

  • 107

volume

  • 4

issue

  • 1

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