A surface exposed O-linked galactose residue destabilises the structure of a folded helix-loop-helix dimer

Org Biomol Chem. 2003 Jul 21;1(14):2455-60. doi: 10.1039/b302847j.

Abstract

A 42-residue glycopeptide Tn-15 and the corresponding reference polypeptide Thr-15 were designed and synthesized to provide a model system for the study of how glycosylation affects the stability of a molten globule-like protein. Tn-15 and Thr-15 fold into hairpin helix-loop-helix motifs that dimerise to form four-helix bundles and the only difference between the sequences is that Tn-15 carries an O-linked N-acetylgalactosamine residue at the side chain of threonine-15 whereas the sequence Thr-15 is unglycosylated. An analysis of the mean residue ellipticities at 222 nm of the two polypeptides and of the alpha-H chemical shift deviations from random coil values showed that glycosylation reduced the helical content of the polypeptides and increased the dissociation constant of the helix-loop-helix dimer to form monomers. The pH dependencies of the helical content of Tn-15 and Thr-15 differed as that of Thr-15 was largely unaffected by pH in the range from pH 4 to pH 10, whereas Tn-15 lost almost half of the helical content at pH 4 upon raising the pH to 10. No single amino acid residue was found to ionize in a way that could explain the observed pH dependence of Tn-15. The temperature dependence of the mean residue ellipticity of Tn-15 revealed a surprising decrease in helicity at 278 K in comparison with that at 293 K, reminiscent of cold denaturation, that was not observed for the reference four-helix bundle Thr-15.

MeSH terms

  • Acetylgalactosamine / chemistry
  • Amino Acid Sequence
  • Amino Acids / chemistry
  • Circular Dichroism
  • Dimerization
  • Galactose / analogs & derivatives*
  • Galactose / chemistry
  • Glycopeptides / chemistry*
  • Glycosylation
  • Helix-Loop-Helix Motifs*
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemistry
  • Temperature

Substances

  • Amino Acids
  • Glycopeptides
  • Peptides
  • Acetylgalactosamine
  • Galactose