Peripheral Membrane Proteins
Proteins of the human Rab (Ras-like proteins in the brain) family are small GTPases and key regulators of cellular processes such as endocytosis. They function as molecular switches between their ‘off’ (GDP-bound) and ‘on’ (GTP-bound) forms and regulate processes on the cellular scale.
Rab5 is an early endosome marker and important for the maturation of early to late endosomes or degradative transport the proteasome, respectively.
The early endosome marker protein Rab5 is incorporating two long chain unsaturated geranylgeranyl anchors at adjacent cysteine residues in the C-terminal hypervariable region (HVR). The HVR is the flexible linker connecting the catalytically active protein G domain and the membrane GG anchor which leads to a multitude of G domain orientations with respect to the membrane surface. Molecular dynamics simulations of the full length Rab5 protein in a physiological six component membrane system revealed persistent electrostatic and hydrogen bonding HVR-PI(3)P (phosphatidylinositol-3-phosphate) interactions and a slowing down of the HVR lateral diffusion with increasing cholesterol as well as PI(3)P fraction.