Polyglutamine fibrillogenesis: the pathway unfolds - PubMed (original) (raw)

Polyglutamine fibrillogenesis: the pathway unfolds

Christopher A Ross et al. Proc Natl Acad Sci U S A. 2003.

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Figures

Figure 1

Figure 1

Schematic representation of proposed structural models for aggregated mutant polyGln. β-Sheet is shown as a zig-zag. Expanded polyGln as an extended antiparallel β-sheet, first described by Max Perutz as a “polar zipper” (a), or as a parallel β-sheet (b). (c) An antiparallel β-hairpin comprised of two β-strands and a single β-turn. A highly compact structure, consisting of four antiparallel random coil (d) or β-strand (e) elements. (f) A parallel β-helix with 20 residues per turn. For simplicity, two polyGln molecules are shown each for a and b, whereas a single polyGln molecule is depicted in c_–_f.

Figure 2

Figure 2

Model of polyGln aggregate initiation and elongation as proposed by Thakur and Wetzel (30). Before the conformational change that initiates disease pathogenesis, mutant polyGln lacks secondary structure. A polyGln monomer undergoes a structural transition to a four-stranded antiparallel β-sheet, with an optimum of seven glutamine residues per β-strand (extended chain). This structured monomer serves as a nucleus for binding of a second unstructured monomer. Binding of the disordered monomer to the ordered nucleus results in acquisition of β-structure in the newly added monomer, providing a new elongation site, and is referred to as template-assisted or “dock-and-lock” elongation. Adapted from Chen et al. (28).

Figure 3

Figure 3

Computer-generated drawing of PGQ9 as a four-stranded antiparallel β-sheet. Only main-chain–main-chain hydrogen bonds were built into the model. The stretches containing nine glutamine residues were built as antiparallel β-strands and the Pro–Gly pairs were built as turns. Atoms are colored as follows: carbons, red; nitrogens, blue; oxygens, red.

Figure 4

Figure 4

Hypothetical pathway of polyGln-mediated aggregation and inclusion formation. Unstructured polyGln monomer undergoes a structural conversion to β-sheet, resulting in the formation of protofibrillar intermediates. This step may proceed through a linear growth mechanism or through assembly of oligomeric intermediates. Protofibril assembly is followed by fibril formation, resulting in the characteristic inclusions observed in polyGln diseases and other amyloid-like diseases.

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