Amyloid-Like Aggregation in Diseases and Biomaterials: Osmosis of Structural Information

Abstract

The discovery that the polypeptide chain has a remarkable and intrinsic propensity to form amyloid-like aggregates endowed with an extraordinary stability is one of the most relevant breakthroughs of the last decades in both protein/peptide chemistry and structural biology. This observation has fundamental implications, as the formation of these assemblies is systematically associated with the insurgence of severe neurodegenerative diseases. Although the ability of proteins to form aggregates rich in cross-β structure has been highlighted by recent studies of structural biology, the determination of the underlying atomic models has required immense efforts and inventiveness. Interestingly, the progressive molecular and structural characterization of these assemblies has opened new perspectives in apparently unrelated fields. Indeed, the self-assembling through the cross-β structure has been exploited to generate innovative biomaterials endowed with promising mechanical and spectroscopic properties. Therefore, this structural motif has become the fil rouge connecting these diversified research areas. In the present review, we report a chronological recapitulation, also performing a survey of the structural content of the Protein Data Bank, of the milestones achieved over the years in the characterization of cross-β assemblies involved in the insurgence of neurodegenerative diseases. A particular emphasis is given to the very recent successful elucidation of amyloid-like aggregates characterized by remarkable molecular and structural complexities. We also review the state of the art of the structural characterization of cross-β based biomaterials by highlighting the benefits of the osmosis of information between these two research areas. Finally, we underline the new promising perspectives that recent successful characterizations of disease-related amyloid-like assemblies can open in the biomaterial field.

Keywords: amino acid aggregation; amyloid aggregates; biomaterials; cross-β structure; glutamine rich structures; peptide-based hydrogels.

FIGURE 1

Schematic representation of the diffraction pattern and of the structure of a typical cross-β assembly.

FIGURE 2

Selected milestones in the atomic-level characterization of cross-β structures related to diseases. The Protein Data Bank code of the related structures is also reported. AD, aSyn, CTE, microED are the abbreviations for Alzheimer Disease, α-Synuclein, Chronic Traumatic Encephalopathy and micro Electro Diffraction, respectively.

FIGURE 3

Progressive increase of structural complexity of the cross-β systems whose structure has been determined at atomic levels starting from the GNNQQNY peptide to the human brain-derived Tau filaments (A). The PDB code of the structures reported from the left to the right of panel (A) are 1yjp, 2kj3, 5oqv, and 6vh7. Ribbons are represented with a color code (blue to red) from the N- to the C-terminus. The panels (B) and (C) report the number of amyloid structures as function of the size deposited in the time interval 2004-2015 and 2016-2020, respectively. The initial search for amyloid-like structures was performed by interrogating the entire PDB (release of October 2020) using as a query the following criteria: Polymer Entity Type = “Protein”; Experimental Method = X-ray diffraction, electron microscopy, electron crystallography, solid-state NMR, fiber diffraction, neutron diffraction, solution scattering; Additional Structure Keywords = “amyloid”; Polymer Entity Sequence Length > 5. The PDB structures identified by the server were then manually checked and their main features were reported in the Supplementary Table 1.

FIGURE 4

Ribbon (A) and ball and stick representation (B) of the doublet Tau Fibril from corticobasal degeneration human brain tissue, the largest cross-β structure currently deposited in the PDB (code 6vh7). Residues are colored as function of their hydrophobicity from gray (polar) to red (apolar). In panel B, posttranslational modification sites are denoted with balls.

FIGURE 5

Ribbon (A) and ball and stick representation (B) structure of the hydrophilic core of cross-beta Orb2 filaments (PDB code 6vps) Residues are colored as function of their hydrophobicity from gray (polar) to red (apolar).

FIGURE 6

Ball and stick representation of the SYSGYS peptide (PDB code 6bwz) from the low-complexity domain of FUS (A). The structure of the GNNQQNY peptide (PDB code 1yjp) is also reported (B).

FIGURE 7

Selected early milestones on self-assembling peptides assuming cross-β structures as elements for fibers and nanotubes, hydrogels and co-assembled biomaterials. Reference for each group are reported following. Fibers and nanotubes: Aβ(16-20) (KLVFF) (Hilbich et al., 1992); EAK16 fibers (Zhang et al., 1993a); modified version of Aβ(1-42) (Seilheimer et al., 1997); protofilaments of Aβ(1-40) (Malinchik et al., 1998); (VT)n peptide fibers (Janek et al., 1999); hIAPP(23-27) (FGAIL) (Tenidis et al., 2000); Val-Val bola-amphiphiles (Kogiso et al., 2000); theory of fiber stabilization (Nyrkova et al., 2000); first crystallographic structure of FF (Görbitz, 2001); peptide-amphiphile nanofibers (Hartgerink et al., 2002); FF aggregation (Reches and Gazit, 2003); model for FF nanotubes (Görbitz, 2006); peptide-PEG fibers (Hamley and Krysmann, 2008). Hydrogels: membranes of EAK16 (Zhang et al., 1993b); EAK16 and RADA16 for cell adhesion (Zhang et al., 1993b); EFK8 HGs matrix (Leon et al., 1998); Boc-Ile5-Ome organogel (Jayakumar et al., 2000); Fmoc D,L dipeptide HGs (Zhang et al., 2003); FmocFF Hydrogel (Mahler et al., 2006); RADA16 as drug vehicle (Nagai et al., 2006); aggregation model of Fmoc-FF (Smith et al., 2008). Co-assembled systems: co-assembled amyloid peptides (Takahashi et al., 2002); co-assemled PAs fibers (Niece et al., 2003); co-assembled ± peptides (Aggeli et al., 2003).

FIGURE 8

Two different views of the F₆ structure obtained from MD studies (A). The interactions at the hydrophobic interfaces are shown (B).

FIGURE 9

Two different views of the (FY)₃ structure obtained from MD studies (A). The interactions at the hydrophobic and hydrophilic interfaces are shown (B).