| Autor: |
Liu G; Carlson School of Chemistry and Biochemistry, Clark University, 950 Main Street, Worcester, MA 01610, USA., Robbins KJ, Sparks S, Selmani V, Bilides KM, Gomes EE, Lazo ND |
| Jazyk: |
angličtina |
| Zdroj: |
Biochemistry [Biochemistry] 2012 May 22; Vol. 51 (20), pp. 4167-74. Date of Electronic Publication: 2012 May 11. |
| DOI: |
10.1021/bi3001616 |
| Abstrakt: |
The formation of amyloid fibrils is associated with incurable diseases including Alzheimer's, Parkinson's, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown partly because of the absence of a clear structural characterization of intermediates. There is experimental evidence, however, for α-helical intermediates that has come primarily from circular dichroism spectroscopy. Here, we strengthen the evidence for helical intermediates by demonstrating helix-dipole effects in the early events of self-assembly. Previously, we showed that capped peptides containing the part of the islet amyloid polypeptide that may be responsible for the initial intermolecular contacts (Acetyl-R(11)LANFLVHSSNNFGA(25)-NH(2) and Acetyl-R(11)LANFLVHSGNNFGA(25)-NH(2) which contains the S20G mutation associated with early onset type 2 diabetes) self-assemble via helical intermediates [Liu et al. (2010) J. Am. Chem. Soc.132, 18223-18232]. We demonstrate here that when the peptides are uncapped, they do not self-assemble as indicated primarily by circular dichroism and nuclear magnetic resonance data. Self-assembly is restored when the charge on α-NH(3)(+) of Arg11 is eliminated but not when the charge on α-COO(-) of Ala25 is removed, consistent with the helicity of the peptides skewed toward the N-terminus. Our results strengthen the hypothesis that α-helical intermediates are on pathway to amyloid formation and indicate that the helix dipole is an attractive target for inhibiting the formation of α-helical assemblies. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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