The RIT1 C-terminus associates with lipid bilayers via charge complementarity

Area of Science:

• Cellular Biology
• Molecular Biology
• Biophysics

Background:

• RIT1 (Ras-like protein 1) is a small GTPase crucial for cellular signaling pathways.
• Mutations in RIT1 are linked to various cancers and developmental disorders.
• Unlike other Ras proteins, RIT1 lacks C-terminal prenylation for membrane attachment.

Purpose of the Study:

• To investigate the mechanism of RIT1's C-terminal peptide (CTP) association with lipid bilayers.
• To understand how RIT1 localizes to the plasma membrane without prenylation.

Main Methods:

• Utilized molecular dynamics simulations.
• Examined the interaction of the RIT1 CTP with different lipid bilayer compositions.

Main Results:

• The RIT1 CTP is intrinsically unstructured.
• Membrane association is dependent on the lipid composition of the bilayer.
• A specific 12-residue region of the CTP strongly binds to anionic bilayers containing phosphatidylserine.
• The CTP termini exhibit flexibility, allowing the RIT1 globular domain to interact at the membrane-water interface.

Conclusions:

• RIT1 utilizes its CTP to anchor to the plasma membrane through specific lipid interactions, particularly with anionic lipids.
• The unstructured nature and lipid-dependent binding of the CTP facilitate RIT1's localization and function at the membrane.
• This mechanism provides insight into the membrane association of prenylation-lacking Ras superfamily members.