López de la Paz M, Goldie K, Zurdo J, Lacroix E, Dobson CM, Hoenger A, Serrano L.
De novo designed peptide-based amyloid fibrils.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16052-7.
PubMed.
An increasing number of neurodegenerative diseases are associated with the formation of amyloid fibrils. Understanding the mechanism of fibril formation thus has obvious clinical value. In addition, knowledge gained in the study of amyloid fibril assembly would increase our understanding of basic aspects of protein folding. Unfortunately, the propensity of amyloid proteins to polymerize into noncrystalline structures has complicated the determination of their atomic structure. Now, in a seminal study by the Tycko group, solid state NMR has been used to provide the most extensive and detailed model of fibril structure yet obtained for the amyloid β-protein (Aβ). The model is attractive because of its consistency with the large body of existing data and its ability to solve the difficult conundrum, based both on NMR and IR data, of how both parallel and antiparallel β-sheets could exist in the same structure. The model predicts coulombic interaction between Asp-23 and Lys-28, a peptide segment long hypothesized to contain a β-turn. Interestingly, substitution of Asp-23 by Asn is associated with a familial form of early onset cerebral amyloid angiopathy in an Iowan kindred. The importance of the central hydrophobic cluster (Leu-17 to Ala-21) and of Met-35 is apparent through inspection, which shows intramolecular packing of the Leu-17, Phe-19, and Met-35 side-chains at the interface between the two β-strands. Similarly, Ile-41, now shown to be critical for the formation of peptide oligomers (see Bitan et al., 2002) would be predicted to interact with His-13 in the anti-parallel β-sheet of the Aβ monomer. Predicted intermolecular associations offer explanations of how mutations producing amino acid substitutions at Glu-22 (the Arctic (Gly), Dutch (Gln), and Italian (Lys) mutations) might affect peptide assembly—there is a disruption of salt-bridges formed between Glu-22 and Lys-16 on each of two antiparallel β-strands in the N-termini of adjoining Aβ monomers. The Tycko model provides a wonderful theoretical foundation for the design of experiments to test the roles of specific amino acids in controlling Aβ assembly. It also offers an "end-stage" structure for simulations of the folding of assembly intermediates.
References:
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB.
Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways.
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5.
PubMed.
Comments
David Geffen School of Medicine at UCLA
An increasing number of neurodegenerative diseases are associated with the formation of amyloid fibrils. Understanding the mechanism of fibril formation thus has obvious clinical value. In addition, knowledge gained in the study of amyloid fibril assembly would increase our understanding of basic aspects of protein folding. Unfortunately, the propensity of amyloid proteins to polymerize into noncrystalline structures has complicated the determination of their atomic structure. Now, in a seminal study by the Tycko group, solid state NMR has been used to provide the most extensive and detailed model of fibril structure yet obtained for the amyloid β-protein (Aβ). The model is attractive because of its consistency with the large body of existing data and its ability to solve the difficult conundrum, based both on NMR and IR data, of how both parallel and antiparallel β-sheets could exist in the same structure. The model predicts coulombic interaction between Asp-23 and Lys-28, a peptide segment long hypothesized to contain a β-turn. Interestingly, substitution of Asp-23 by Asn is associated with a familial form of early onset cerebral amyloid angiopathy in an Iowan kindred. The importance of the central hydrophobic cluster (Leu-17 to Ala-21) and of Met-35 is apparent through inspection, which shows intramolecular packing of the Leu-17, Phe-19, and Met-35 side-chains at the interface between the two β-strands. Similarly, Ile-41, now shown to be critical for the formation of peptide oligomers (see Bitan et al., 2002) would be predicted to interact with His-13 in the anti-parallel β-sheet of the Aβ monomer. Predicted intermolecular associations offer explanations of how mutations producing amino acid substitutions at Glu-22 (the Arctic (Gly), Dutch (Gln), and Italian (Lys) mutations) might affect peptide assembly—there is a disruption of salt-bridges formed between Glu-22 and Lys-16 on each of two antiparallel β-strands in the N-termini of adjoining Aβ monomers. The Tycko model provides a wonderful theoretical foundation for the design of experiments to test the roles of specific amino acids in controlling Aβ assembly. It also offers an "end-stage" structure for simulations of the folding of assembly intermediates.
References:
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB. Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5. PubMed.
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