Structural insights into functional and pathological amyloid - PubMed (original) (raw)

Review

Structural insights into functional and pathological amyloid

Frank Shewmaker et al. J Biol Chem. 2011.

Abstract

Amyloid is traditionally viewed as a consequence of protein misfolding and aggregation and is most notorious for its association with debilitating and chronic human diseases. However, a growing list of examples of "functional amyloid" challenges this bad reputation and indicates that many organisms can employ the biophysical properties of amyloid for their benefit. Because of developments in the structural studies of amyloid, a clearer picture is emerging about what defines amyloid structure and the properties that unite functional and pathological amyloids. Here, we review various amyloids and place them within the framework of the latest structural models.

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Figures

FIGURE 1.

Filamentous aggregates can be composed of various arrangements of their constituent proteins. Very different structures are proposed for various amyloids. A, parallel in-register β-sheet structures are composed of individual polypeptides stacking in-register every ∼4.7 Å along the fibril axis (common to many full-length proteins in pathological amyloids). B, antiparallel β-sheet structures are also composed of polypeptides stacking every ∼4.7 Å, but β-strands alternately run in opposite directions (observed primarily in amyloids composed of short polypeptide sequences). C, β-helices are composed of a single polypeptide wrapping around an axis, forming intramolecular parallel β-sheets (likely the structural basis of two functional amyloids). D, some β-sheet-rich proteins can linearly assemble into filamentous structures by other mechanisms, including domain swapping. E, amyloids composed of parallel in-register β-strands form continuous β-sheets that run the length of the fiber. The dimensions and packing densities of such amyloids suggest that the fibrils are composed of sheets folded upon themselves, as has been shown with Aβ (16). Complementary side chains may form steric zippers that stabilize the interlocking sheets. In the case of yeast prion amyloids, multiple and different sheet folds may underlie the variant phenomenon.

FIGURE 2.

Structures of pathological and functional amyloids. A, schematic representation of a parallel in-register β-sheet structure of Aβ1–40 (99). The Protein Data Bank file was kindly provided by Rob Tycko. The fibril is composed of two protofibrils (a single protofibril is shown in the lower half of A), which are each composed of stacked Aβ1–40 peptides in-register with the preceding and following peptides. B, schematic representation of HET-s β-helical amyloid (residues 223–283 from Protein Data Bank code 2KJ3) (100). The monomers alternate between blue and yellow, revealing that each polypeptide provides two β-strands that wrap around the long axis of the fiber.

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Structural insights into functional and pathological amyloid - PubMed (original) (raw)