Helix-Dipole Effects in Peptide Self-Assembly to Amyloid

Abstract

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.

Role of Site-Specific Asparagine Deamidation in Islet Amyloid Polypeptide Amyloidogenesis: Key Contributions of Residues 14 and 21

“…Finally, deamidation at positions 31 and 35 did not affect the time necessary to reach the high-energy nucleus, the rate of amyloid growth, or the morphology of the assemblies. These data reinforce the concept that the 11–25 segment mediates the initial intermolecular interactions leading to amyloid assembly. , …”

“…These data reinforce the concept that the 11−25 segment mediates the initial intermolecular interactions leading to amyloid assembly. 45,46 It was previously reported that nontargeted and spontaneous (aging) Asn deamidation accelerates IAPP self-assembly and alters fibrils structure. 18 However, the Asn residues subjected to deamidation were not identified.…”

Conformational Distribution and α-Helix to β-Sheet Transition of Human Amylin Fragment Dimer

“…34 Their further experimental studies strengthened the existence of α -helical intermediates in amyloid formation of hIAPP(11–25) and full-length hIAPP peptides. 35,36…”

Helix Dipole and Membrane Electrostatics Delineate Conformational Transitions in the Self-Assembly of Amyloidogenic Peptides

“…The success of deconvolution, however, depends primarily on the availability of reference databases that include CD spectra of proteins of known structure . Because current databases do not include CD spectra of peptide or protein assemblies, deconvolution may not be applicable to the analysis of CD spectra of amyloidogenic peptides and proteins. ,, Nonetheless, if the protein assembly of interest is predominantly α-helical, a suitable alternative to deconvolution is to use eq , which has been successfully applied to determine the helix content of α-helical assemblies: where [θ] 222nm is the mean-residue ellipticity of the peptide at 222 nm and [θ] 222nm,100%helix is the calculated mean-residue ellipticity at 222 nm of a peptide with a helix content of 100%. To calculate the latter, we used the following equation derived by Chen et al: where [θ] 222nm,infinite helix is the mean-residue ellipticity at 222 nm for an infinite helix determined by Chen et al to be equal to −37 400 deg cm 2 dmol –1 , k is a wavelength-dependent factor that is equal to 2.5 at 222 nm, and n helix is the number of residues in the helix.…”

“…Here, we investigated a fragment of IAPP that forms an α-helix − in order to explore the role of the helix dipole in the self-assembly of amyloidogenic peptides in the presence of membranes. IAPP is a 37-residue polypeptide (Figure ) that is cosecreted with insulin from pancreatic β-cells.…”