Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils?
The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for "normal" left-hand-helical filaments and below pH 2 for "reversed" right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left-twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross-β-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-α-lactalbumin, HET-s (218-289) prion, and a short polypeptide fragment of transthyretin, TTR (105-115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases.
Department of Chemistry, University at Albany, State University of New York , 1400 Washington Avenue, Albany, New York 12222, United States.
Dmitry
D
Kurouski
Xuefang
X
Lu
Ludmila
L
Popova
William
W
Wan
Maruda
M
Shanmugasundaram
Gerald
G
Stubbs
Rina K
RK
Dukor
Igor K
IK
Lednev
Laurence A
LA
Nafie
D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D008855:Microscopy, Electron, Scanning; D009113:Muramidase / Q000737:chemistry; D017433:Protein Structure, Secondary; D013237:Stereoisomerism; D014732:Vibration
D000682:Amyloid; D009113:Muramidase