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Amyloid
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Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.
name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.
The remainder of this article will use the biophysical context.
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oid is characterized by a cross-beta sheet quaternary structure; that is, the beta-strands of the stacked beta-sheets come from different protein monomers and align perpendicular to the axis of the fibril.
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Encyclopedia
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various other neurodegenerative diseases.
Definition
The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.
- The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting beta sheet structure. Common to most cross-beta type structures they are generally identified by apple-green birefringence when stained with congo red and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component, resulting in complex, and sometimes inhomogeneous structures. Recently this definition has come into question as some classic, amyloid species have been observed in distinctly intracellular locations.
- A more recent, biophysical definition is broader, including any polypeptide which polymerizes to form a cross-beta structure, in vivo, or in vitro. Some of these, although demonstrably cross-beta sheet, do not show some classic histopathological characteristics such as the Congo red birefringence. Microbiologists and biophysicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.
The remainder of this article will use the biophysical context.
Diseases featuring amyloids
Non-disease and functional amyloids
- Native amyloids in organisms
- Curli E. coli Protein (curlin)
- Chaplins from Streptomyces coelicolor
- Podospora Anserina Prion Het-s
- Malarial coat protein
- Spider silk (some but not all spiders)
- Mammalian melanosomes (pMel)
- Tissue-type plasminogen activator (tPA), a hemodynamic factor
- Proteins and peptides engineered to make amyloid
Amyloid biophysics
Amyloid is characterized by a cross-beta sheet quaternary structure; that is, the beta-strands of the stacked beta-sheets come from different protein monomers and align perpendicular to the axis of the fibril. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the "gold-standard" test to see if a structure contains cross-beta fibres is by placing a sample in an X-ray diffraction beam. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.
Amyloid polymerization (aggregation or non-covalent polymerization) is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce amylin, an amyloidogenic peptide associated with type II diabetes, but in rats and mice prolines are substituted in critical locations and amyloidogenesis does not occur.
There are two broad classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of Yeast and mammalian prions, as well as Huntington's disease. When peptides are in a beta-sheet conformation, particularly when the residues are parallel and in-register (causing alignment), glutamines can brace the structure by forming intrastrand hydrogen bonding between its amide carbonyls and nitrogens. In general, for this class of diseases, toxicity correlates with glutamine content. This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a C. elegans model system with engineered polyglutamine peptides.
Other polypeptides and proteins such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association. Among the hydrophobic residues, aromatic amino-acids are found to have the highest amyloidogenic propensity.
For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is observed in vitro and possibly in vivo. This phenomenon is important since it would explain interspecies prion propagation and differential rates of prion propagation, as well as a statistical link between Alzheimer's and type 2 diabetes. In general, the more similar the peptide sequence the more efficient cross-polymerization is, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization. Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.
Amyloid pathology
The reasons for amyloid association with disease is unclear. In some cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process. An emerging consensus implicates prefibrillar intermediates, rather than mature amyloid fibers, in causing cell death.
Studies have shown that amyloid deposition is associated with mitochondrial dysfunction and a resulting generation of reactive oxygen species (ROS), which can initiate a signaling pathway leading to apoptosis .
Histological staining
Clinically, amyloid diseases are typically identified by a change in the fluorescence intensity of planar aromatic dyes such as thioflavin T or congo red. Congo red positivity remains the gold standard for diagnosis of amyloidosis. This is generally attributed to the environmental change, as these dyes intercalate between beta-strands. Congophilic amyloid plaques generally cause apple-green birefringence when viewed through crossed polarimetric filters. To avoid nonspecific staining, other histology stains, such as the hematoxylin and eosin stain, are used to quench the dyes' activity in other places such as the nucleus where the dye might bind. Modern antibody technology and immunohistochemistry has made specific staining easier, but often this can cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.
External links
- at SciVee
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- at Boston University
- at InformaWorld
- (www.amyloidosisaustralia.org)
- at amyloidosis.org
- at ucl.ac.uk
- at University of California, Berkeley
- amyloidosisresearchfoundation.org
- at National Institute of Health
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- Covering strucutre, mechanisms of action and kinetics of amyloid fibrils.
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