Foldability of a Natural De Novo Evolved Protein

Structure. 2017 Nov 7;25(11):1687-1696.e4. doi: 10.1016/j.str.2017.09.006. Epub 2017 Oct 12.

Abstract

The de novo evolution of protein-coding genes from noncoding DNA is emerging as a source of molecular innovation in biology. Studies of random sequence libraries, however, suggest that young de novo proteins will not fold into compact, specific structures typical of native globular proteins. Here we show that Bsc4, a functional, natural de novo protein encoded by a gene that evolved recently from noncoding DNA in the yeast S. cerevisiae, folds to a partially specific three-dimensional structure. Bsc4 forms soluble, compact oligomers with high β sheet content and a hydrophobic core, and undergoes cooperative, reversible denaturation. Bsc4 lacks a specific quaternary state, however, existing instead as a continuous distribution of oligomer sizes, and binds dyes indicative of amyloid oligomers or molten globules. The combination of native-like and non-native-like properties suggests a rudimentary fold that could potentially act as a functional intermediate in the emergence of new folded proteins de novo.

Keywords: amyloid oligomer; conformational specificity; de novo protein; de novo protein-coding gene; molten globule; partially folded protein; protein folding; structural evolution.

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • DNA, Intergenic / chemistry*
  • DNA, Intergenic / genetics
  • DNA, Intergenic / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Protein Biosynthesis
  • Protein Conformation, beta-Strand
  • Protein Denaturation
  • Protein Folding
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Thermodynamics

Substances

  • BSC4 protein, S cerevisiae
  • DNA, Intergenic
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins