Illuminating the off-pathway nature of the molten globule folding intermediate of an α-β parallel protein

PLoS One. 2012;7(9):e45746. doi: 10.1371/journal.pone.0045746. Epub 2012 Sep 21.

Abstract

Partially folded protein species transiently form during folding of most proteins. Often, these species are molten globules, which may be on- or off-pathway to the native state. Molten globules are ensembles of interconverting protein conformers that have a substantial amount of secondary structure, but lack virtually all tertiary side-chain packing characteristics of natively folded proteins. Due to solvent-exposed hydrophobic groups, molten globules are prone to aggregation, which can have detrimental effects on organisms. The molten globule observed during folding of the 179-residue apoflavodoxin from Azotobacter vinelandii is off-pathway, as it has to unfold before native protein can form. Here, we study folding of apoflavodoxin and characterize its molten globule using fluorescence spectroscopy and Förster Resonance Energy Transfer (FRET). Apoflavodoxin is site-specifically labeled with fluorescent donor and acceptor dyes, utilizing dye-inaccessibility of Cys69 in cofactor-bound protein. Donor (i.e., Alexa Fluor 488) is covalently attached to Cys69 in all apoflavodoxin variants used. Acceptor (i.e., Alexa Fluor 568) is coupled to Cys1, Cys131 and Cys178, respectively. Our FRET data show that apoflavodoxin's molten globule forms in a non-cooperative manner and that its N-terminal 69 residues fold last. In addition, striking conformational differences between molten globule and native protein are revealed, because the inter-label distances sampled in the 111-residue C-terminal segment of the molten globule are shorter than observed for native apoflavodoxin. Thus, FRET sheds light on the off-pathway nature of the molten globule during folding of an α-β parallel protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoproteins / chemistry*
  • Azotobacter vinelandii / chemistry*
  • Flavodoxin / chemistry*
  • Fluorescence Resonance Energy Transfer
  • Guanidine / chemistry
  • Models, Molecular
  • Protein Denaturation
  • Protein Refolding*
  • Protein Stability
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Staining and Labeling

Substances

  • Apoproteins
  • Flavodoxin
  • apoflavodoxin
  • Guanidine

Grants and funding

The Netherlands Organization for Scientific Research (NWO) supported this work (grant number 700.56.002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.