Journal article
Aβ40-Lactam(D23/K28) Models a Conformation Highly Favorable for Nucleation of Amyloid
Biochemistry (Easton), Vol.44(16), pp.6003-6014
04/26/2005
DOI: 10.1021/bi0474867
PMID: 15835889
Abstract
Recent solid-state NMR data (I) demonstrate that A beta sub(1-40) adopts a conformation in amyloid fibrils with two in-register, parallel beta -sheets, connected by a bend structure encompassing residues D super(23)VGSNKG super(29), with a close contact between the side chains of Asp23 and Lys28. We hypothesized that forming this bend structure might be rate-limiting in fibril formation, as indicated by the lag period typically observed in the kinetics of A beta sub(1-40) fibrillogenesis. We synthesized A beta sub(1-40)-Lactam(D23/K28), a congener A beta sub(1-40) peptide that contains a lactam bridge between the side chains of Asp23 and Lys28. A beta sub(1-40)-Lactam(D23/K28) forms fibrils similar to those formed by A beta sub(1-40). The kinetics of fibrillogenesis, however, occur without the typical lag period, and at a rate approximately 1000-fold greater than is seen with A beta sub(1-40) fibrillogenesis. The strong tendency toward self-association is also shown by size exclusion chromatography in which A beta sub(1-40)-Lactam(D23/K28) forms oligomers even at concentrations of approximately 1-5 mu M. Under the same conditions, A beta sub(1-40) shows no detectable oligomers by size exclusion chromatography. Our data suggest that A beta sub(1-40)-Lactam(D23/K28) could bypass an unfavorable folding step in fibrillogenesis, because the lactam linkage "preforms" a bendlike structure in the peptide. Consistent with this view A beta sub(1-40) growth is efficiently nucleated by A beta sub(1-40)-Lactam(D23/K28) fibril seeds.
Details
- Title: Subtitle
- Aβ40-Lactam(D23/K28) Models a Conformation Highly Favorable for Nucleation of Amyloid
- Creators
- Kimberly L SciarrettaDavid J GordonAneta T PetkovaRobert TyckoStephen C Meredith
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.44(16), pp.6003-6014
- DOI
- 10.1021/bi0474867
- PMID
- 15835889
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Language
- English
- Date published
- 04/26/2005
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984093482102771
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