Folding, Misfolding, and Amyloid Protofibril Formation of WW Domain FBP28

Rapid amyloid fiber formation from the fast-folding WW domain FBP28.

The WW domains are small proteins that contain a three-stranded, antiparallel beta-sheet. The 40-residue murine FBP28 WW domain rapidly formed twirling ribbon-like fibrils at physiological temperature and pH, with morphology typical of amyloid fibrils. These ribbons were unusually wide and well ordered, making them highly suitable for structural studies. Their x-ray and electron-diffraction pat...

Dominant folding pathways of a WW domain.

We investigate the folding mechanism of the WW domain Fip35 using a realistic atomistic force field by applying the Dominant Reaction Pathways approach. We find evidence for the existence of two folding pathways, which differ by the order of formation of the two hairpins. This result is consistent with the analysis of the experimental data on the folding kinetics of WW domains and with the resu...

Amyloid-β Protofibril Formation and Neurotoxicity Implications for Alzheimer’s Disease

The ensemble folding kinetics of the FBP28 WW domain revealed by an all-atom Monte Carlo simulation in a knowledge-based potential.

In this work, we apply a detailed all-atom model with a transferable knowledge-based potential to study the folding kinetics of Formin-Binding protein, FBP28, which is a canonical three-stranded β-sheet WW domain. Replica exchange Monte Carlo simulations starting from random coils find native-like (Cα RMSD of 2.68 Å) lowest energy structure. We also study the folding kinetics of FBP28 WW domain...

Amyloid protofibril is highly voluminous and compressible.

We report here results of the first direct measurement of partial volume and compressibility changes of a protein as it forms an amyloid protofibril. We use a high precision density meter and an ultrasonic velocity meter on a solution of intrinsically denatured, disulfide-deficient variant of hen lysozyme, and follow the time-dependent changes in volume and compressibility, as the protein spont...