p21ras is modified by a farnesyl isoprenoid

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Oncogenic Ras proteins require membrane association for cellular transformation.
• Ras proteins are synthesized as cytosolic precursors and processed to mature, membrane-localized forms.
• A conserved Cys-Ali-Ali-Xaa motif at the Ras COOH terminus is critical for processing.

Purpose of the Study:

• To investigate the post-translational modification of Ras proteins at their COOH terminus.
• To determine if Ras proteins are modified by palmitoylation or isoprenoid addition, like yeast mating factors.
• To explore the role of this modification in Ras membrane association and transforming activity.

Main Methods:

• Comparative analysis of Ras protein processing with yeast a-factor mating hormone precursor.
• Investigating the COOH-terminal Cys-Ali-Ali-Xaa sequence for post-translational modifications.
• Assessing the impact of identified modifications on Ras membrane localization and biological function.

Main Results:

• Ras proteins, analogous to yeast peptides, undergo farnesylation at the COOH-terminal cysteine.
• This farnesylation appears to be a key modification, rather than palmitoylation, for Ras processing.
• Farnesylation is implicated as crucial for Ras membrane association and its oncogenic transforming activity.

Conclusions:

• The Cys-Ali-Ali-Xaa motif signals farnesylation for Ras proteins, a modification shared with yeast mating factors.
• Farnesylation is essential for the proper membrane localization and oncogenic function of Ras proteins.
• This finding clarifies Ras protein processing and suggests potential therapeutic targets.