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#Rab GTPases

2 public questions tagged with this topic.

Protein Sorting and Trafficking

Which of these regulates vesicle targeting and fusion?

Accurate membrane flow despite overlapping SNARE compatibility requires additional targeting layer beyond SNARE pairing. Rab small GTPases provide master regulation representing largest Ras superfamily with over 70 members humans each localized via C-terminal hypervariable domain plus geranylgeranyl modifications added by Rab geranylgeranyl transferase and REP. Localized activation by cognate GEFs DENN, TRAPP, Mon1-Ccz1 converts GDP to GTP exposing switch regions binding diverse effectors including long coiled-coil tethers golgin-84, GM130, p115 bridging distances, multisubunit complexes HOPS, CORVET, exocyst, GARP proofreading SNARE assembly, and kinesin dynein adaptors like RILP linking vesicle to microtubule tracks delivering vesicle to correct domain before fusion. Targeting precedes SNARE engagement adding essential specificity beyond combinatorial code which alone would permit promiscuous fusion. Mannosidase enzymes modify N-glycans in Golgi lumen; KDEL receptors retrieve ER proteins via COPI; SNARE disassembly factors work post-fusion. Genetic lesion Rab5 causing giant early endosomes or Rab7 causing delayed lysosomal degradation exemplifies regulatory role in targeting and fusion control essential for organelle homeostasis and membrane identity.

Ref: Stenmark, Nat Rev Mol Cell Biol: Rab GTPases coordinate vesicle targeting and fusion.

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Protein Sorting and Trafficking

What is the main function of Rab GTPases in protein trafficking?

Rab family is largest branch of Ras superfamily, more than sixty members in mammals, each localized to specific organelle defining compartment identity and regulating sequential vesicle traffic steps. C-terminal cysteine geranylgeranylation anchors Rab to cytosolic face of membranes. In active GTP-bound conformation, Rab recruits diverse effectors: tethering complexes EEA1 for Rab5 early endosomes, GARP and golgins for retrograde traffic, exocyst for Rab11 recycling vesicles, and motor adaptors linking vesicles to kinesin for anterograde or dynein-dynactin for retrograde movement along microtubules. Guanine exchange factors like Rabex-5 activate Rabs on designated membranes, while RabGAPs containing TBC domain stimulate hydrolysis converting to GDP form releasing effectors and allowing extraction by GDI for recycling. This cycle ensures specificity so COPII vesicles from ER fuse only with cis-Golgi, not lysosomes, and provides timing for endosomal maturation Rab5 to Rab7 conversion. Unlike importin transporting through nuclear pores or kinases phosphorylating SNAREs to regulate fusion, Rab orchestrates upstream vesicle targeting, motility and tethering coordinated with SNARE-mediated final fusion ensuring fidelity of trafficking pathways and organelle biogenesis.

Ref: Zerial & McBride, Nature Rev Mol Cell Biol 2: 2001, Rab GTPases Control Vesicle Targeting.

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