Probing solvent accessibility of transthyretin amyloid by solution NMR spectroscopy.
The human plasma protein transthyretin (TTR) may form fibrillar protein deposits that are associated with both inherited and idiopathic amyloidosis. The present study utilizes solution nuclear magnetic resonance spectroscopy, in combination with hydrogen/deuterium exchange, to determine residue-specific solvent protection factors within the fibrillar structure of the clinically relevant variant, TTRY114C. This novel approach suggests a fibril core comprised of the six beta-strands, A-B-E-F-G-H, which retains a native-like conformation. Strands C and D are dislocated from their native edge region and become solvent-exposed, leaving a new interface involving strands A and B open for intermolecular interactions. Our results further support a native-like intermolecular association between strands F-F' and H-H' with a prolongation of these beta-strands and, interestingly, with a possible shift in beta-strand register of the subunit assembly. This finding may explain previous observations of a monomeric intermediate preceding fibril formation. A structural model based on our results is presented.
Olofsson
Anders
A
Department of Molecular Biology, Umeå University, Umeå SE-901 87, Sweden.
Ippel
Johannes H
JH
Wijmenga
Sybren S
SS
Lundgren
Erik
E
Ohman
Anders
A
D000682:Amyloid / Q000737:chemistry*; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013058:Mass Spectrometry; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D011228:Prealbumin / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013053:Spectrophotometry; D013696:Temperature; D013997:Time Factors; D014466:Ultraviolet Rays
D000682:Amyloid; D011228:Prealbumin; D006859:Hydrogen