Binding interactions in early- and late-stage amyloid aggregates of TTR(105-115).
One of the central aims of amyloid research is to identify chemical and structural features that confer amyloidogenic propensity. In this study, we use Saturation Transfer Difference (STD) NMR spectroscopy to acquire an atom-specific map of the interactions between soluble and aggregated Transthyretin peptide (TTR(105-115)) in early- and late-stage amyloidogenesis. Atomic Force Microscopy (AFM) was used to monitor the transition of early-stage samples, containing protofilaments, to late-stage samples composed of fully-mature fibrils. Progressive aggregation was accompanied by an increase in the correlation time tau(c) of soluble TTR(105-115) as indicated by (1)H NMR line broadening, but no significant change in the (1)H chemical shifts. The STD profile of backbone amide protons is in good agreement with an earlier computational study predicting hydrogen bonding propensity for each residue in small TTR(105-115) aggregates (Paci et al., J. Mol. Biol. (2004) 555-569). The STD profiles of C(alpha) and C(beta) protons identify a central aliphatic region of the peptide, Ala108-Leu111, that plays a crucial, but different role in early- and late-stage amyloidogenesis. In general, the STD profiles of early and fully-mature samples are dissimilar, suggesting different mechanisms of self-assembly in protofilaments and mature amyloid fibrils. The early-stage mechanism appears to be more dependent on main-chain hydrogen bonding, while the late-stage mechanism involves an increased number of interactions between bulky side chains.
Liang
Yanfang
Y
York University, Department of Chemistry, Toronto, ON, Canada M3J 1P6.
Jasbi
Shohreh Zahedi
SZ
Haftchenary
Sina
S
Morin
Sylvie
S
Wilson
Derek J
DJ
D000682:Amyloid / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D010455:Peptides / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry*; D011485:Protein Binding
D000682:Amyloid; D010455:Peptides; D011228:Prealbumin