A novel prenyl-polybasic domain code determines lipid-binding specificity of the K-Ras membrane anchor

Area of Science:

• Molecular biology
• Cellular biology
• Biophysics

Background:

• Ras proteins, including K-Ras4B, need to localize to the plasma membrane (PM) for their biological functions.
• The K-Ras4B membrane anchor, a combination of a prenylated cysteine and a polybasic domain (PBD), was traditionally thought to bind membranes non-specifically.
• Recent findings indicate K-Ras4B exhibits high specificity for phosphatidylserine (PtdSer).

Purpose of the Study:

• To investigate the role of the PBD sequence and prenyl lipid in determining K-Ras anchor specificity for plasma membrane lipids.
• To further explore the combinatorial code governing K-Ras4B lipid binding and its impact on biological function.

Main Methods:

• Utilized all-atom molecular dynamics simulations to analyze PM interactions.
• Examined the behavior of geranylgeranylated K-Ras4B polybasic domain mutants at the PM.

Main Results:

• The PBD sequence and prenyl lipid type together determine the specificity of K-Ras anchor binding to specific membrane lipids.
• Mutations in the PBD, such as Lys177 or Lys178 to glutamine, alter lipid binding preference from PtdSer to phosphoinositol 4,5-bisphosphate (PIP2).
• Modifications to the prenyl anchor (farnesyl to geranylgeranyl) or PBD lysines (to arginines) also change lipid binding specificity.

Conclusions:

• The precise PBD sequence and prenyl lipid are critical determinants of K-Ras anchor lipid sorting specificity.
• This specificity influences K-Ras4B localization and, consequently, its biological function and signaling output.