A polymetamorphic protein

Katie L. Stewart, Eric D. Dodds, Vicki H. Wysocki, Matthew Hj Cordes

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Arc repressor is a homodimeric protein with a ribbon-helix-helix fold. A single polar-tohydrophobic substitution (N11L) at a solvent-exposed position leads to population of an alternate dimeric fold in which 310 helices replace a β-sheet. Here we find that the variant Q9V/N11L/R13V (S-VLV), with two additional polar-to-hydrophobic surface mutations in the same β-sheet, forms a highly stable, reversibly folded octamer with approximately half the α-helical content of wild-type Arc. At low protein concentration and low ionic strength, S-VLV also populates both dimeric topologies previously observed for N11L, as judged by NMR chemical shift comparisons. Thus, accumulation of simple hydrophobic mutations in Arc progressively reduces fold specificity, leading first to a sequence with two folds and then to a manifold bridge sequence with at least three different topologies. Residues 9-14 of S-VLV form a highly hydrophobic stretch that is predicted to be amyloidogenic, but we do not observe aggregates of higher order than octamer. Increases in sequence hydrophobicity can promote amyloid aggregation but also exert broader and more complex effects on fold specificity. Altered native folds, changes in fold coupled to oligomerization, toxic pre-amyloid oligomers, and amyloid fibrils may represent a near continuum of accessible alternatives in protein structure space.

Original languageEnglish (US)
Pages (from-to)641-649
Number of pages9
JournalProtein Science
Volume22
Issue number5
DOIs
Publication statusPublished - May 2013

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Keywords

  • Fold switching
  • Polar-to-hydrophobic substitution
  • Sequence-structure relationship
  • Structural degeneracy
  • Structural evolution

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Stewart, K. L., Dodds, E. D., Wysocki, V. H., & Cordes, M. H. (2013). A polymetamorphic protein. Protein Science, 22(5), 641-649. https://doi.org/10.1002/pro.2248