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.
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Rab5 is an early endosome marker and important for the maturation of early to late endosomes or degradative transport the proteasome, respectively.
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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.