Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains

Rafayel A. Azizyan, Adriana Garro, Zinaida Radkova, Alexey Anikeenko, Anastasia Bakulina, Christian Dumas, Andrey V. Kajava

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

In many disease-related and functional amyloids, the amyloid-forming regions of proteins are flanked by globular domains. When located in close vicinity of the amyloid regions along the chain, the globular domains can prevent the formation of amyloids because of the steric repulsion. Experimental tests of this effect are few in number and non-systematic, and their interpretation is hampered by polymorphism of amyloid structures. In this situation, modeling approaches that use such a clear-cut criterion as the steric tension can give us highly trustworthy results. In this work, we evaluated this steric effect by using molecular modeling and dynamics. As an example, we tested hybrid proteins containing an amyloid-forming fragment of Aβ peptide (17–42) linked to one or two globular domains of GFP. Searching for the shortest possible linker, we constructed models with pseudo-helical arrangements of the densely packed GFPs around the Aβ amyloid core. The molecular modeling showed that linkers of 7 and more residues allow fibrillogenesis of the Aβ-peptide flanked by GFP on one side and 18 and more residues when Aβ-peptide is flanked by GFPs on both sides. Furthermore, we were able to establish a more general relationship between the size of the globular domains and the length of the linkers by using analytical expressions and rigid body simulations. Our results will find use in planning and interpretation of experiments, improvement of the prediction of amyloidogenic regions in proteins, and design of new functional amyloids carrying globular domains.

Original languageEnglish
Pages (from-to)3835-3846
Number of pages12
JournalJournal of Molecular Biology
Volume430
Issue number20
DOIs
Publication statusPublished - 12 Oct 2018

Keywords

  • aggregation
  • amyloids
  • fibrillogenesis
  • protein structure
  • rigid body simulation
  • PROTEIN
  • MOLECULAR-STRUCTURE
  • POLYMORPHISM
  • MODEL
  • PEPTIDE
  • ORGANIZATION
  • FIBRILS
  • FILAMENTS
  • DYNAMICS
  • AGGREGATION
  • Peptide Fragments/chemistry
  • Amyloid beta-Peptides/chemistry
  • Protein Domains
  • Protein Interaction Domains and Motifs
  • Recombinant Fusion Proteins/chemistry
  • Amino Acid Sequence
  • Amyloid/chemistry
  • Models, Molecular
  • Protein Binding
  • Protein Conformation

Fingerprint

Dive into the research topics of 'Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains'. Together they form a unique fingerprint.

Cite this