Transition of Metastable Cross-α Crystals into Cross-β Fibrils by β-Turn Flipping

Abstract

The ensemble of native, folded state was once considered to represent the global energy minimum of a given protein sequence. More recently, the discovery of the cross-β amyloid state revealed that deeper energy minima exist, often associated with pathogenic, fibrillar deposits, when the concentration of proteins reaches a critical value. Fortunately, a sizable energy barrier impedes the conversion from native to pathogenic states. However, little is known about the structure of the related transition state. In addition, there are indications of polymorphism in the amyloidogenic process. Here, we report the first evidence of the conversion of metastable cross-α-helical crystals to thermodynamically stable cross-β-sheet-like fibrils by a de novo designed heptapeptide. Furthermore, for the first time, we demonstrate at atomic resolution that the flip of a peptide plane from a type I to a type II′ turn facilitates transformation to cross-β structure and assembly of a dry steric zipper. This study establishes the potential of a peptide turn, a common protein secondary structure, to serve as a principal gatekeeper between a native metastable folded state and the amyloid state.

The Amphibian Antimicrobial Peptide Uperin 3.5 is a Cross-α/Cross-β Chameleon Functional Amyloid

“…Martin, Carver and co-workers previously pointed on a potential chameleon propensity of uperin 3.5 41 , and discussed the role of helices as intermediates to aggregation 33,41,76,77 along with the potential contribution of intermolecular helix-helix interactions in the formation of a fibrillation nuclei 41 . A thermalinduced cross-α/cross-β transition was previously reported in a synthetic self-assembling heptapeptide, suggested to occur via an intermediate turn motif 33 . In addition, a dipeptide proteinmimics, containing triazole linkages as peptide-bond surrogate, formed β-sheet rich structures in crystals, while heat-induced polymerization into a pseudoprotein revealed transition into helical sheets resembling the cross-α configuration 37 .…”

“…Recently, various synthetic peptides, unnatural enantiomers and protein-mimics have been shown to form an architecture resembling cross-α [33][34][35][36][37] .…”

Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules

“…Aberrant assembly events are associated with a range of disorders, and they can involve polymerization of natively folded protein molecules, 2 as in sickle cell anemia, 12 or aggregation which is accompanied by significant conformational changes, as exemplified by amyloid diseases. 13 , 14 Understanding the molecular basis and consequences of such protein–protein interaction (PPI) pathways and identifying methods for their modulation 15 − 20 therefore have implications for the treatment of disease, 21 as well as in the development of new biomaterials, where protein self-assembly can be exploited to yield structures with defined architectures or novel biomechanical properties. 22 , 23 However, manipulating and defining the mechanisms of self-assembly is challenging, due to the transient nature and heterogeneity (in mass and structure) of oligomeric intermediates.…”

The substitution of a single amino acid with its enantiomer for control over the adjuvant activity of self-assembling peptides

“…5 More and more smart supramolecular hydrogels have been developed, and they have shown excellent results in nanomedicine, [6][7][8][9] tissue engineering, 10,11 vaccine adjuvants, [12][13][14] and disease detection. [15][16][17] The self-assembly properties of peptides are sequence-dependent 18,19 and they are also inuenced by further ne-tuning of the chemical structure; [20][21][22][23][24] this leads to further variations of self-assembled nanostructures and biofunctions. Fine-tuning the chemical structure of a peptide, especially substituting a single amino acid for its enantiomer, to control its self-assembly behavior is sometimes difficult to understand, but there is evidence that it makes a lot of sense.…”