Structure formation during translocon-unassisted co-translational membrane protein folding

Sci Rep. 2017 Aug 14;7(1):8021. doi: 10.1038/s41598-017-08522-9.

Abstract

Correctly folded membrane proteins underlie a plethora of cellular processes, but little is known about how they fold. Knowledge of folding mechanisms centres on reversible folding of chemically denatured membrane proteins. However, this cannot replicate the unidirectional elongation of the protein chain during co-translational folding in the cell, where insertion is assisted by translocase apparatus. We show that a lipid membrane (devoid of translocase components) is sufficient for successful co-translational folding of two bacterial α-helical membrane proteins, DsbB and GlpG. Folding is spontaneous, thermodynamically driven, and the yield depends on lipid composition. Time-resolving structure formation during co-translational folding revealed different secondary and tertiary structure folding pathways for GlpG and DsbB that correlated with membrane interfacial and biological transmembrane amino acid hydrophobicity scales. Attempts to refold DsbB and GlpG from chemically denatured states into lipid membranes resulted in extensive aggregation. Co-translational insertion and folding is thus spontaneous and minimises aggregation whilst maximising correct folding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / metabolism
  • Endopeptidases / chemistry*
  • Endopeptidases / metabolism
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Molecular Dynamics Simulation
  • Protein Folding*

Substances

  • Bacterial Proteins
  • DNA-Binding Proteins
  • DsbB protein, Bacteria
  • Escherichia coli Proteins
  • GlpG protein, E coli
  • Membrane Proteins
  • Endopeptidases