title: Self-assembling properties of peptides derived from TDP-43 C-terminal fragment.
abstract: Two highly fibrillogenic peptide sequences (MNFGAFSINP and EDLIIKGISV) were previously reported in the C-terminal fragment (CTF) of TDP-43 (220-414), a protein recently implicated in neuro-degenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). It was observed that the sequences MNFGAFS and EDLIIKG harbor their respective fibrillogenic domains. Here, the self-assembling properties of peptides obtained by systematic deletion of residues from these two sequences were investigated with the help of light scattering, thioflavin T fluorescence, transmission electron microscopy, and circular dichroism spectroscopy. It was found that the pentapeptide NFGAF and the tetrapeptide DLII are the shortest fibrillogenic sequences from MNFGAFS and EDLIIKG, respectively. Structure function studies revealed that self-assembly of the peptides is largely governed by hydrophobic interactions. Both NFGAF and DLII formed hydrogels based on a complex fibrillar network, at relatively low concentrations, and of remarkable strength and stability. Of particular interest was DLII, a rare aliphatic tetrapeptide that formed a hydrogel at a concentration of 1 mg/mL in less than an hour. Interestingly, various other tetrapeptides based on DLII (YLII, KLII, NLII, and LIID) also formed hydrogels of comparable physical properties, suggesting that an amphipathic peptide design based on the hydrophobic LII motif and a single residue polar terminus is highly favorable for hydrogelation. Peptides discovered in this study, especially DLII and its variants, are some of the shortest ever reported to show such structural and functional features, suggesting that they can be useful templates for the design of peptide-based soft materials.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Akash
authors.initials: A
authors.lastname: Saini
authors.forename: Virander S
authors.initials: VS
authors.lastname: Chauhan
mesh_terms: D000595:Amino Acid Sequence; D052160:Benzothiazoles; D004268:DNA-Binding Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D020100:Hydrogels; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D066329:Protein Aggregates; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013844:Thiazoles
chemical_list: D052160:Benzothiazoles; D004268:DNA-Binding Proteins; D020100:Hydrogels; D066329:Protein Aggregates; D013844:Thiazoles; C009462:thioflavin T