The contribution of individual residues of an aggregative hexapeptide derived from the human γD-crystallin to its amyloidogenicity

Malak Abu-Hussien, Guru Krishnakumar Viswanathan, Luba Simhaev, Ashim Paul, Hamutal Engel, Ehud Gazit, Daniel Segal

Research output: Contribution to journalArticlepeer-review

Abstract

Human γD-crystallin protein is abundant in the lens and is essential for preserving lens transparency. With age the protein may lose its native structure resulting in the formation of cataract. We recently reported an aggregative peptide, 41Gly-Cys-Trp-Met-Leu-Tyr46 from the human γD-crystallin, termed GDC6, exhibiting amyloidogenic properties in vitro. Here, we aimed to determine the contribution of each residue of the GDC6 to its amyloidogenicity. Molecular dynamic (MD) simulations revealed that the residues Trp, Leu, and Tyr played an important role in the amyloidogenicity of GDC6 by facilitating inter-peptide main-chain hydrogen bonds, and π-π interactions. MD predictions were further validated using single-, double- and triple-alanine-substituted GDC6 peptides in which their amyloidogenic propensity was individually evaluated using complementary biophysical techniques including Thioflavin T assay, turbidity assay, CD spectroscopy, and TEM imaging. Results revealed that the substitution of Trp, Leu, and Tyr together by Ala completely abolished aggregation of GDC6 in vitro, highlighting their importance in the amyloidogenicity of GDC6.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalInternational Journal of Biological Macromolecules
Volume201
DOIs
StatePublished - 15 Mar 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 Elsevier B.V.

Keywords

  • Amyloid aggregation
  • Cataract
  • GDC6 peptide
  • Self-assembly
  • γD-crystallin

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