title: A polymetamorphic protein.
abstract: Arc repressor is a homodimeric protein with a ribbon-helix-helix fold. A single polar-to-hydrophobic 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Stewart
authors.forename: Eric D
authors.initials: ED
authors.lastname: Dodds
authors.forename: Vicki H
authors.initials: VH
authors.lastname: Wysocki
authors.forename: Matthew H J
authors.initials: MH
authors.lastname: Cordes
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D051017:Apoptosis Regulatory Proteins