Initial conformational changes of human transthyretin under partially denaturing conditions.
Human transthyretin (TTR) is an amyloidogenic protein. The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils. Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization. Hence, tertiary structural changes within the monomers after the dissociation are essential for the amyloid formation. These tertiary structural changes can be facilitated by partial denaturation. To probe the conformational changes under the partially denaturing conditions, five independent trajectories were collected for the wild-type (WT) and its pathogenic variants at 300 and 350 K, resulting in simulations that totaled 59 ns. Under these conditions, L55P variant is more labile than the wild-type and V30M variant. We have observed that the D strand of WT-TTR is trapped in two local minima: the native conformation and the amyloidogenic fold that resembles the surface loop of residues 54-55 of L55P variant. In the tetrameric state, the F strand is bent with large separations at the F-F' interface. This strand becomes flatter in the monomeric state, which may facilitate the formation of new F-F' interface with possible prolonged hydrogen bonds and/or shift in beta-strand register in the fibril state. During the unfolding process, the anticorrelated motion between the strands H and G as well as the strands H and A pulls the H strand out of the inner sheet plane, leading to a more twisted inner sheet. Our simulation has provided important detailed structural information about the partially unfolded state of TTR that may be related to the amyloidogenic intermediates.
Yang
Mingfeng
M
Gustaf H. Carlson School of Chemistry and Biochemistry, Clark University, Worcester, Massachusetts 01610, USA.
Lei
Ming
M
Bruschweiler
Rafael
R
Huo
Shuanghong
S
D000682:Amyloid / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011108:Polymers / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry*; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013696:Temperature; D013816:Thermodynamics
D000682:Amyloid; D011108:Polymers; D011228:Prealbumin