Long-range Regulation of Partially Folded Amyloidogenic Peptides

Abstract

neurodegeneration involves abnormal aggregation of intrinsically disordered amyloidogenic peptides (iDps), usually mediated by hydrophobic protein-protein interactions. there is mounting evidence that formation of α-helical intermediates is an early event during self-assembly of amyloid-β42 (Aβ42) and α-synuclein (αS) iDps in Alzheimer's and parkinson's disease pathogenesis, respectively. However, the driving force behind on-pathway molecular assembly of partially folded helical monomers into helical oligomers assembly remains unknown. Here, we employ extensive molecular dynamics simulations to sample the helical conformational sub-spaces of monomeric peptides of both Aβ42 and αS. our computed free energies, population shifts, and dynamic cross-correlation network analyses reveal a common feature of long-range intra-peptide modulation of partial helical folds of the amyloidogenic central hydrophobic domains via concerted coupling with their charged terminal tails (n-terminus of Aβ42 and C-terminus of αS). The absence of such inter-domain fluctuations in both fully helical and completely unfolded (disordered) states suggests that long-range coupling regulates the dynamicity of partially folded helices, in both Aβ42 and αS peptides. the inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in partially folded helical monomers. this approach could be applied to study the broad range of amyloidogenic peptides, which could provide a new path to curbing pathogenic aggregation of partially folded conformers into oligomers, by inhibition of sites far from the hydrophobic core. Protein conformational disorders including Alzheimer's (AD) and Parkinson's disease (PD) present the hallmark features of misfolding, self-assembly, and accumulation of monomeric precursor peptides known as intrinsically disordered proteins (IDPs) or amyloidogenic peptides such as amyloid-β, Aβ (implicated in AD) and α-synuclein, αS (in PD) 1. Low molecular weight soluble oligomers are thought to be neurotoxic in the self-assembly pathway 2 , and a number of experiments suggest their formation may proceed via α-helical oligomeric intermediates 3-5. Partially folded helical conformers (monomers) have been reported to be on-pathway to fibril formation 6,7. Consequently, the tendency to form helical oligomers (through helix-helix associations) may be imprinted within the minor populations of aggregation-prone partially folded helical monomers 3,6-8 that both Aβ and αS display in membrane-free aqueous solution 9,10 , and which arise via conformational exchanges between non-aggregating helically folded and completely unfolded states. Formation of partially folded intermediates has also long been correlated with aggregation and is identified as a key step in fibrillation 11,12. A powerful mathematical model based on kinetic state transitions for Aβ structural evolution during fibrillogenesis has been able to reproduce the experimentally observed helical intermediates 13. The energy landscapes of globula...

Effect of an Amyloidogenic SARS-COV-2 Protein Fragment on α-Synuclein Monomers and Fibrils

“…The 140-residue long α-synuclein monomer consists of three domains: (i) an amphipathic N-terminal region (residues 1–60), where most disease-causing familial mutations are located and which binds to membranes; (ii) a hydrophobic nonamyloid-β component (NAC) region (residues 61–95) that is thought to be the core region for aggregation; and (iii) a disordered negatively charged C-terminal region (residues 96–140). − Both N- and C-terminal regions can affect α-synuclein aggregation and fibril propagation. While the negatively charged C-terminal region plays a crucial role in suppressing α-synuclein aggregation, − N-terminal residues are essential for fibril formation. , A helix-rich model of the α-synuclein monomer structure has been resolved by solution NMR in the micellar environment and is deposited in the Protein Data Bank (PDB) under PDB ID: 1XQ8 . Using molecular dynamics simulations we study how SK9 interacts with α-synuclein and whether SK9 changes the conformational ensemble of the monomer, potentially modifying oligomerization and hastening the formation of a critical nucleus for seeding fibrils.…”

Single-Particle Resolution of Copper-Associated Annular α-Synuclein Oligomers Reveals Potential Therapeutic Targets of Neurodegeneration

“…The computed α-Syn monomer dynamics shows the formation of α-helices in the N-terminus with a β-hairpin formed close to the NAC region. Recent studies on monomers and dimers have indicated that α-Syn samples a heterogeneous ensemble of interconverting conformations in an aqueous solution, including parallel and antiparallel β-sheets and transient α-helical conformations, ,− with long stretches of α-helices predicted to impede pathogenic aggregation of α-Syn. − However, compared to α-Syn in bulk water, the reduced conformational freedom of α-Syn at the gold–water interface may stabilize fibril-like morphologies, as also noted previously for adsorption of amyloid-β-42 peptide on gold and amyloid-β-42 protofibrils on graphene . For the Cu 2+ /monomer (1:1) complex, the maximum height is ∼3.4 nm with a narrow distribution showing that the high affinity of Cu 2+ for NT compacts the monomer (Figure b) via additional Cu 2+ –CT interactions (Figure S12a ) and is close to the maximum height of spherical particles when exposed to 1 μM Cu 2+ obtained from our AFM experiments (∼3.25 nm) (see Figure c, red histogram).…”

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

“…Previously, we have shown that a Sirtuin ligand, SirReal2, is particularly effective in inducing a structural rearrangement of the active site that exposes an adjacent binding pocket and that results in hyperacetylation of the microtubule network (Figure 3) [62]. Allosteric regulation has been reported for PPIs involving SYN, which is based on targeting SYN outside the interface [63]. In fact, the inter-domain coupling suggests a form of intra-molecular allosteric regulation of the aggregation trigger in the partially folded helical monomers (Figure 4).…”