Quartz 4

Rab Cycle

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Rab Cycle

Rab protein은 membrane과 cytosol 사이를 cycle하면서 vesicle transport를 조절한다. 이 cycle은 vesicle과 target membrane에서 일어나며, vesicle identity와 targeting specificity를 제공한다.

Rab protein의 구조와 특성

Monomeric GTPase

  • 60개 이상의 member (mammalian cell)
  • Largest subfamily of monomeric GTPase
  • 각 Rab이 specific organelle/vesicle에 associate

Membrane localization

각 Rab protein은 특정 compartment에 localize:

Rab proteinOrganelle/Vesicle
Rab1ER, Golgi complex
Rab2cis Golgi network
Rab3ASynaptic vesicle, secretory vesicle
Rab4/Rab11Recycling endosome
Rab5Early endosome, plasma membrane
Rab6Medial and trans Golgi
Rab7Late endosome
Rab8Cilia
Rab9Late endosome, TGN

Basic Rab cycle

GDP-bound state (inactive, cytosolic)

  • Rab-GDP는 cytosol에서 soluble
  • **GDI (GDP Dissociation Inhibitor)**에 binding
  • GDI가 Rab을 soluble하게 유지

Membrane recruitment and activation

Step 1: GEF binding

  • Membrane-bound Rab GEF가 Rab-GDP에 binding
  • 종종 coat component가 GEF recruit

Step 2: GDP → GTP exchange

  • GEF가 GDP release 촉매
  • GTP binding (high cytosolic concentration)

Step 3: Membrane insertion

  • GTP binding으로 Conformational change
  • Lipid anchor (prenyl group) exposure
  • Membrane에 insert
  • GDI release

Active state (GTP-bound, membrane)

Rab effector recruitment

  • Active Rab-GTP가 다양한 Rab effector에 binding
  • Effector type:
    • Tethering protein
    • Motor protein
    • Lipid-modifying enzyme
    • SNARE-binding protein
    • Scaffold protein

Inactivation and membrane release

Step 1: GAP activation

  • Rab GAP가 GTP hydrolysis 촉진
  • Often at target membrane

Step 2: GTP → GDP

  • Conformational change
  • Effector release
  • Lipid anchor retraction

Step 3: GDI binding

  • GDI가 Rab-GDP에 binding
  • Membrane에서 extract
  • Cytosol로 return

Vesicle에서의 Rab activation

Initial activation

Transport vesicle 형성 시:

  1. Coat component가 specific Rab GEF recruit
  2. Rab activation
  3. Vesicle에 Rab-GTP display

Multiple consequences

Molecular marker

  • Vesicle identity 표시
  • Target membrane recognition에 사용

Motor protein recruitment

  • Kinesin, dynein, myosin 등
  • Microtubule/actin filament을 따라 이동

Tethering protein recruitment

  • Long-range capture of vesicle
  • Initial contact with target membrane

Target membrane에서의 Rab function

Rab-associated domain formation

Positive feedback mechanism

  1. Rab GEF가 membrane에서 Rab activate
  2. Active Rab이 더 많은 같은 Rab GEF recruit
  3. More Rab activation
  4. Rab5 예시: PI 3-kinase activate → PI(3)P production
  5. PI(3)P가 Rab effector (tethering protein 포함) binding stabilize
  6. Large, specialized membrane patch 형성

Organelle identity 부여

Rab-associated domain이 organelle의 특성 결정:

  • Incoming vesicle traffic (tethering protein, SNARE)
  • Outgoing vesicle traffic (coat protein)
  • Enzyme activity (lipid kinase, etc.)
  • Positioning (motor protein)

Vesicle tethering and docking

Long-range tethering

  • Rab effector (filamentous protein)가 vesicle capture
  • 200 nm까지 reach 가능
  • Vesicle의 Rab-GTP와 target membrane의 Rab effector 상호작용. Rab effector는 target membrane의 Rab-GTP와도 상호작용. 여기서 두 Rab는 같은 종류여야함.

SNARE-mediated docking

  • Rab effector가 SNARE를 selective하게 binding
  • v-SNARE와 t-SNARE pairing 촉진
  • Membrane fusion 유도

Rab inactivation

  • Fusion 후 Rab GAP가 Rab-GTP hydrolyze
  • Rab-GDP가 membrane에서 dissociate
  • GDI에 의해 cytosol로 return

GTP hydrolysis rate의 조절

Active Rab의 concentration과 duration은 GTP hydrolysis rate에 의해 조절:

  • Slow hydrolysis → High steady-state Rab-GTP
  • Fast hydrolysis → Low steady-state Rab-GTP
  • Domain size와 activity 조절

생리적 중요성

Rab cycle의 dysregulation:

  • Vesicle mis-targeting
  • Organelle identity loss
  • Trafficking defect
  • Disease (e.g., Parkinson’s disease와 Rab7L1 mutation)

Graph View

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