Membrane anchoring of the DIRAS3 N-terminal extension permits tumor suppressor function.

ABSTRACT: DIRAS3 is an imprinted tumor suppressor gene encoding a GTPase that has a distinctive N-terminal extension (NTE) not found in other RAS proteins. This NTE and the prenylated C-terminus are required for DIRAS3-mediated inhibition of RAS/MAP signaling and PI3K activity at the plasma membrane. In this study, we applied biochemical, biophysical, and computational methods to characterize the structure and function of the NTE. The NTE peptide recognizes phosphoinositides PI(3,4,5)P₃ and PI(4,5)P₂ with rapid kinetics and strong affinity. Lipid binding induces NTE structural change from disorder to amphipathic helix. Mass spectrometry identified N-myristoylation of DIRAS3. All-atom molecular dynamic simulations predict DIRAS3 could adhere to the membrane through both t

SUBMITTER: Liang X 

PROVIDER: S-EPMC10616557 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature