Self-Assembly of a Nine-Residue Amyloid-Forming Peptide Fragment of SARS Corona Virus E-Protein: Mechanism of Self Aggregation and Amyloid-Inhibition of hIAPP

Abstract

Molecular self-assembly, a phenomenon widely observed in nature, has been exploited through organic molecules, proteins, DNA and peptides to study complex biological systems. These self-assembly systems may also be used in understanding the molecular and structural biology which can inspire the design and synthesis of increasingly complex biomaterials. Specifically, use of these building blocks to investigate protein folding and misfolding has been of particular value since it can provide tremendous insights into peptide aggregation related to a variety of protein misfolding diseases, or amyloid diseases (e.g. Alzheimer’s disease, Parkinson’s disease, type-II diabetes). Herein, the self-assembly of TK9, a 9 residue peptide of the extra membrane C-terminal tail of the SARS Corona virus envelope, and its variants were characterized through biophysical, spectroscopic and simulated studies, and it was confirmed that the structure of these peptides influence their aggregation propensity, hence, mimicking amyloid proteins. TK9, which forms a beta-sheet rich fibril, contains a key sequence motif that may be critical for beta-sheet formation, thus making it an interesting system to study amyloid fibrillation. TK9 aggregates were further examined through simulations to evaluate the possible intra- and inter peptide interactions at the molecular level. These self-assembly peptides can also serve as amyloid inhibitors through hydrophobic and electrophilic recognition interactions. Our results show that TK9 inhibits the fibrillation of hIAPP, a 37 amino acid peptide implicated in the pathology of type-II diabetes. Thus, biophysical and NMR experimental results have revealed a molecular level understanding of peptide folding events, as well as the inhibition of amyloid-protein aggregation are reported.

Pre-structured hydrophobic peptide β-strands: A universal amyloid trap?

“…There have been a few examples of peptides with no sequence similarity that are capable of interacting with amyloidogenic peptides. For example, Ghosh et al demonstrated that a nine residue peptide taken from the SARS corona virus ( Table 1) was able to inhibit hAM amyloidogenesis [131]. However, it is worth noting that the inhibitor itself was shown to be capable of aggregation albeit at a much slower rate than hAM.…”

Structural insights of a self-assembling 9-residue peptide from the C-terminal tail of the SARS corona virus E-protein in DPC and SDS micelles: A combined high and low resolution spectroscopic study

“…Specifically, the "VYVY" motif of the peptide inserted deeply into the hydrophobic core of the DPC lipids as revealed by PRE experiments. It is noteworthy to mention that this same motif of TK9 had been shown earlier to self-assemble in solution to form beta-sheet rich amyloid fibrillar ordered nano-assemblies [10]. Thus, the peptide sequence that underlies the host specificity and affinity also directed helical conformation in the presence of membrane that leads to the downstream aggregation of the protein units in forming the pentameric [9] structure.…”

“…In our previous study, we highlighted the significance of a short stretch of 9 residues (TK9) derived from the host-membrane associating C-terminal end of the E-protein [10]. The study demonstrated that TK9 self-assembles in aqueous solution and more specifically the aromatic residues in the motif 'VYVY' accelerate formation of the amyloidogenic deposit [10].…”

“…In our previous study, we highlighted the significance of a short stretch of 9 residues (TK9) derived from the host-membrane associating C-terminal end of the E-protein [10]. The study demonstrated that TK9 self-assembles in aqueous solution and more specifically the aromatic residues in the motif 'VYVY' accelerate formation of the amyloidogenic deposit [10]. In the present study, we now focus on the structural aspect of the peptide in the presence of the host membrane mimicking micelles and large unilamellar vesicles (LUVs) to understand the biological significance of this amyloidogenic stretch in the viral pathogenesis.…”

Self‐Assembly and Neurotoxicity of β‐Amyloid (21–40) Peptide Fragment: The Regulatory Role of GxxxG Motifs

“…Further, scanning electron microscopy images of the peptide aggregates at their saturation phase confirmed the occurrence of amyloid aggregation (Figure S2). The fibrils exhibited dendritic morphology, consisting of long branched rod‐like fibers . While the branching of Aβ40, AV20, G25 L, and G29 L aggregates were random, G33 L and G37 L aggregates were more uniform and linear in nature.…”