Lipid-binding characteristics of the polybasic carboxy-terminal sequence of K-ras4B

Biochemistry. 1998 May 19;37(20):7640-8. doi: 10.1021/bi973077h.


We have examined the association with lipid vesicles of fluorescent lipidated peptides based on the farnesylated, polybasic carboxy-terminal region of mature K-ras4B, which functions physiologically as an autonomous plasma membrane-targeting motif. While the peptides bind to neutral lipid (phosphatidylcholine/phosphatidylethanolamine) vesicles with relatively low affinity, the vesicle-binding affinity increases exponentially as increasing amounts of anionic lipids are incorporated into the vesicle bilayers. Competitive vesicle-binding experiments reveal that the K-ras4B carboxy-terminal sequence accordingly discriminates strongly between lipid surfaces of differing surface charge, such that two lipid bilayers differing in anionic lipid content by 10 mol % will show a 45-fold preferential accumulation of the lipidated peptide in the more negatively charged surface. At the same time, the carboxyl-terminal region of K-ras4B exhibits no preferential binding to particular anionic lipids, including the polyanionic species phosphatidylinositol-4'-phosphate and phosphatidylinositol-4',5'-bisphosphate, beyond that predicted on the basis of surface-charge effects. The K-ras4B carboxyl-terminal sequence dissociates rapidly (with half-times of seconds or less) from lipid bilayers containing up to 40 mol % anionic lipid. These results suggest that the targeting of the mature K-ras4B carboxy-terminus to the plasma membrane, if it is based on interactions with plasma membrane lipids, is not mediated by a kinetic-trapping mechanism or by specific binding to particular anionic lipids but may rest on the sensitive surface potential-sensing function of this region of the protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anions
  • Cholesterol / chemistry
  • Humans
  • Kinetics
  • Lipid Bilayers / chemistry
  • Lipid Metabolism*
  • Mice
  • Peptide Fragments / chemistry
  • Peptides
  • Phosphatidylcholines / chemistry
  • Phosphatidylserines / chemistry
  • Protein Binding
  • Protein Prenylation
  • Proto-Oncogene Proteins p21(ras) / chemistry*
  • Static Electricity
  • Xenopus laevis


  • Anions
  • Lipid Bilayers
  • Peptide Fragments
  • Peptides
  • Phosphatidylcholines
  • Phosphatidylserines
  • 1,2-dioleoylphosphatidylserine
  • Cholesterol
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)