In Vitro-Evolved Peptides Bind Monomeric Actin and Mimic Actin-Binding Protein Thymosin-β4

ACS Chem Biol. 2021 May 21;16(5):820-828. doi: 10.1021/acschembio.0c00825. Epub 2021 Apr 12.

Abstract

Actin is the most abundant protein in eukaryotic cells and is key to many cellular functions. The filamentous form of actin (F-actin) can be studied with help of natural products that specifically recognize it, as for example fluorophore-labeled probes of the bicyclic peptide phalloidin, but no synthetic probes exist for the monomeric form of actin (G-actin). Herein, we have panned a phage display library consisting of more than 10 billion bicyclic peptides against G-actin and isolated binders with low nanomolar affinity and greater than 1000-fold selectivity over F-actin. Sequence analysis revealed a strong similarity to a region of thymosin-β4, a protein that weakly binds G-actin, and competition binding experiments confirmed a common binding region at the cleft between actin subdomains 1 and 3. Together with F-actin-specific peptides that we also isolated, we evaluated the G-actin peptides as probes in pull-down, imaging, and competition binding experiments. While the F-actin peptides were applied successfully for capturing actin in cell lysates and for imaging, the G-actin peptides did not bind in the cellular context, most likely due to competition with thymosin-β4 or related endogenous proteins for the same binding site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / chemistry
  • Actins / chemistry*
  • Binding Sites
  • Binding, Competitive
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • Marine Toxins / chemistry
  • Microfilament Proteins / chemistry*
  • Oxazoles / chemistry
  • Peptide Library
  • Peptides, Cyclic / chemistry*
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Thymosin / chemistry*

Substances

  • Actins
  • Marine Toxins
  • Microfilament Proteins
  • Oxazoles
  • Peptide Library
  • Peptides, Cyclic
  • mycalolide B
  • thymosin beta(4)
  • Thymosin