Glycine rich segments adopt polyproline II helices: Implications for biomolecular condensate formation

M. Mompeán, B. S. McAvan, Sara Sofia Félix, Mario Treviño, Javier Oroz, R. López-Sánchez, David Pantoja-Uceda, Eurico José Cabrita, A. J. Doig, Douglas V. Laurents

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Abstract

Many intrinsically disordered proteins contain Gly-rich regions which are generally assumed to be disordered. Such regions often form biomolecular condensates which play essential roles in organizing cellular processes. However, the bases of their formation and stability are still not completely understood. Based on NMR studies of the Gly-rich H. harveyi “snow flea” antifreeze protein, we recently proposed that Gly-rich sequences, such as the third “RGG” region of Fused in Sarcoma (FUS) protein, may adopt polyproline II helices whose association might stabilize condensates. Here, this hypothesis is tested with a polypeptide corresponding to the third RGG region of FUS. NMR spectroscopy and molecular dynamics simulations suggest that significant populations of polyproline II helix are present. These findings are corroborated in a model peptide Ac-RGGYGGRGGWGGRGGY-NH2, where a peak characteristic of polyproline II helix is observed using CD spectroscopy. Its intensity suggests a polyproline II population of 40%. This result is supported by data from FTIR and NMR spectroscopies. In the latter, NOE correlations are observed between the Tyr and Arg, and Arg and Trp side chain hydrogens, confirming that side chains spaced three residues apart are close in space. Taken together, the data are consistent with a polyproline II helix, which is bent to optimize interactions between guanidinium and aromatic moieties, in equilibrium with a statistical coil ensemble. These results lend credence to the hypothesis that Gly-rich segments of disordered proteins may form polyproline II helices which help stabilize biomolecular condensates.

Original languageEnglish
Article number108867
JournalArchives of Biochemistry and Biophysics
Volume704
DOIs
Publication statusPublished - 15 Jun 2021

Keywords

  • Bimolecular condensates
  • CD Spectroscopy
  • FTIR spectroscopy
  • Molecular dynamics
  • NMR spectroscopy
  • Polyproline II helices

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