An amyloidogenic hexapeptide from the cataract-associated γD-crystallin is a model for the full-length protein and is inhibited by naphthoquinone-tryptophan hybrids
| Autor: | Guru KrishnaKumar Viswanathan, Ashim Paul, Ehud Gazit, Daniel L. Segal, Esraa Haj, Malak Abu-Hussien |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Amyloid Molecular Conformation Peptide 02 engineering and technology Naphthalenes Protein Aggregation Pathological Biochemistry Cataract Protein Aggregates Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Structural Biology Crystallin Native state Humans Amino Acid Sequence gamma-Crystallins Cytotoxicity Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Dose-Response Relationship Drug Tryptophan General Medicine 021001 nanoscience & nanotechnology Recombinant Proteins eye diseases Naphthoquinone In vitro chemistry Biophysics sense organs 0210 nano-technology Oligopeptides |
| Zdroj: | International Journal of Biological Macromolecules. 157:424-433 |
| ISSN: | 0141-8130 |
| DOI: | 10.1016/j.ijbiomac.2020.04.079 |
| Popis: | The eye lens is rich in proteins called crystallins, whose native conformation is crucial for preserving its transparency. With aging, crystallins may be exposed to environmental changes, which could lead to their aggregation and eventually to cataract development. Human γD-crystallin, among the most abundantly expressed γ-crystallins in the lens, was shown to form amyloid aggregates under denaturing conditions in vitro. However, the exact mechanism of aggregation remains to be clearly defined. Here, using prediction algorithms and biophysical methods, we identified a hexapeptide 41GCWMLY46 as a most aggregative fragment in human γD-crystallin. Two aromatic naphthoquinone-tryptophan hybrid molecules (NQTrp and Cl-NQTrp), inhibited the in vitro aggregation of this hexapeptide as well as full-length γD-crystallin in a dose-dependent manner, plausibly facilitated by hydrogen bonding and aromatic contacts with the hydrophobic residues. The two compounds had no toxic effect toward retinal cell culture and reduced the cytotoxicity induced by aggregates of the hexapeptide. In addition, NQTrp and Cl-NQTrp were able to disassemble pre-formed aggregates of the hexapeptide and the full-length γD-crystallin. Our results indicate that the amyloidogenic hexapeptide is a useful model for screening inhibitors of γD-crystallin and that the NQTrp hybrid scaffolds may serve as leads for developing new drugs for treating cataract. |
| Databáze: | OpenAIRE |
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