Conformational evolution of polymorphic amyloid assemblies

Abstract

The morphological diversity of amyloid assemblies has complicated the development of disease therapies and the design of novel biomaterials for decades. Here we review the conformational evolution of amyloids from the initial liquid-liquid phase separation into the oligomeric particle phase to the nucleation of the more ordered assembly phases. With mounting evidence that the assemblies emerging from the oligomeric phases may not be stable in solution and undergo further structural transitions, we propose the concept of conformational evolution, where mutations may occur at the ends or on the surface of the pre-existing fibers and different morphologies are under selection throughout the assembly process.

Control over the fibrillization yield by varying the oligomeric nucleation propensities of self-assembling peptides

“…4d) for which we used NMR distance restraints and dihedral restraints 40 . The antiparallel alignment was also in line with 15 N R1 rho measurements that probe the slow microsecond dynamics of the assembly (Fig. S4).…”

“…2D 13 C-13 C and 2D CαN for peptide assignments were also performed at similar conditions 37 . 2D Ca(N)H experiments for 15 NT 1rho relaxation studies were performed at 950 MHz magnetic field strength with 60 kHz. 13 C was detected in the indirect dimension because of spectral overlap in the 15 N dimension.…”

“…However, increasing evidence shows that, to overcome the huge desolvation barrier, rather than a spontaneous thermodynamic process, supramolecular assembly of amphiphilic peptides proceed via a multistep 11 pathway, along which metastable oligomeric states are first formed before conversion to supramolecular nanofibers ( Fig. 1a) [12][13][14][15][16][17][18] . This implies that the state of the intermediates in the assembly pathway also exert critical influence over the outcome of the peptide self-assembly 19,20 .…”

“…Structure determination of the basic building blocks of the SLP fibers. a Superposition of 2D ssNMR PARIS 13 C-13 C spectra of 13 C,15 N-(Val1, Val2, Leu6, Leu7)-labeled SLP1 acquired with 50 (gray) and 700 ms (magenta) magnetization transfer. Intramolecular and intermolecular correlations are labeled in black and blue, respectively.…”

The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order

“…Interplay of Q zipper structure and surface tension may drive the accumulation of pre-amyloid oligomers Soluble oligomers accumulate during the aggregation of pathologic length polyQ and/or Htt in vitro (Auer et al, 2008;Hsieh et al, 2017;Levin et al, 2014;Liang et al, 2018;Li et al, 2010;Sil et al, 2018;Vitalis and Pappu, 2011;Yamaguchi et al, 2005;Zanjani et al, 2020), in cultured cells (Olshina et al, 2010;Takahashi et al, 2008), and in the brains of patients (Legleiter et al, 2010;Sathasivam et al, 2010), and are likely culprits of proteotoxicity (Kim et al, 2016;Leitman et al, 2013;Lu and Palacino, 2013;Matlahov and van der Wel, 2019;Takahashi et al, 2008;Wetzel, 2020).…”