Cell Biology: Rab Proteins in Vesicle Trafficking
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Questions and Answers

What is the modification that soluble proteins destined for lysosomes acquire in the Golgi?

  • ApoB-100 modification
  • M6P modification (correct)
  • Tyrosine modification
  • Clathrin modification
  • What is the function of the M6P receptor in the Golgi?

  • To degrade macromolecules
  • To assemble clathrin coats
  • To recognize and bind M6P-modified proteins (correct)
  • To recycle LDL receptors
  • What is the purpose of Rab proteins in organelle trafficking?

  • To provide identity labels for organelles (correct)
  • To facilitate protein folding in the ER
  • To modify sugar structures in proteins
  • To form vesicles for protein transport
  • What is the fate of the M6P receptor after the cargo dissociates from it in the late endosomes?

    <p>It is transported back to the trans-Golgi via a vesicle</p> Signup and view all the answers

    What is the function of COPII vesicles in protein transport?

    <p>To collect and transport proteins from the ER to the cis Golgi</p> Signup and view all the answers

    What is the purpose of enzyme replacement therapy (ERT) in Gaucher disease?

    <p>To administer M6P-modified forms of missing enzymes to lysosomes</p> Signup and view all the answers

    What happens to Rab-GDP after it is released from the membrane?

    <p>It is recycled and re-used</p> Signup and view all the answers

    What is the role of AP2 in the LDL receptor pathway?

    <p>To interact with the cytosolic domain of the LDL receptor</p> Signup and view all the answers

    What is the role of the KDEL sequence in COPI vesicle formation?

    <p>It binds to the KDEL receptor on the Golgi membrane</p> Signup and view all the answers

    What is the fate of LDL after it dissociates from its receptor in the endosomes?

    <p>It is passed to lysosomes for degradation</p> Signup and view all the answers

    What is the consequence of defective Rab proteins?

    <p>Diseases arise from non-normal organelles</p> Signup and view all the answers

    What is the function of SNARE proteins in organelle trafficking?

    <p>To mediate vesicle fusion</p> Signup and view all the answers

    What is the function of lysosomes in the cell?

    <p>To degrade imported materials and recycle macromolecules</p> Signup and view all the answers

    What is the role of COPI vesicles in protein transport?

    <p>To transport proteins from the Golgi to the ER</p> Signup and view all the answers

    Why do some lysosomal enzymes escape to the plasma membrane?

    <p>Due to imperfect targeting of M6P receptors</p> Signup and view all the answers

    What is the purpose of mannose-6-phosphate (M6P) in protein transport?

    <p>To direct proteins to lysosomes</p> Signup and view all the answers

    What is the timeframe in which ion channels open and close?

    <p>less than 1 ms</p> Signup and view all the answers

    What is the function of VGCaCs in the cell?

    <p>to transduce membrane potential changes as a messenger</p> Signup and view all the answers

    What is the function of nicotinic acetylcholine receptors in muscle?

    <p>to respond to ACh released from pre-synaptic fibres</p> Signup and view all the answers

    What is the structure of voltage-gated cation channels?

    <p>24 membrane spanning regions arranged around a central pore</p> Signup and view all the answers

    How do Ca2+ channels exhibit ion selectivity?

    <p>through a narrow selectivity filter allowing cations to pass through single file</p> Signup and view all the answers

    What is the shape of the residues at the tip of TMD6 in closed channels?

    <p>a tepee shape</p> Signup and view all the answers

    What is the function of VGNa/KCs in the cell?

    <p>to act as cables</p> Signup and view all the answers

    What is the function of GABA/glycine receptors in the CNS?

    <p>to mediate most synaptic transmission</p> Signup and view all the answers

    Study Notes

    Vesicle Trafficking

    • Proteins are packed into vesicles for trafficking from the ER.
    • Rab proteins, a type of small G-protein, serve as identity labels for organelles.
    • Rab is active when bound to GTP and inactive when bound to GDP.

    Rab Activation and Inactivation

    • Rab-GDP is recruited to intracellular membrane.
    • Activation occurs when the host membrane has specific proteins to form Rab-GTP, allowing proof-reading.
    • Recognition of Rab-GTP by another organelle is stabilized if it can hydrolyze Rab-GTP to form Rab-GDP.
    • Rab-GDP is then released from the membrane to be re-used.

    Diseases Caused by Defective Rabs

    • Charcot Marie tooth disease 2B is caused by a Rab7 mutation.
    • Legionnaire's disease is caused by a Rab1 mutation.

    Protein Trafficking

    • Proteins folded and N-glycosylated in the ER are collected into COPII vesicles.
    • COPII vesicles move to the cis Golgi, where sugar structures of proteins are trimmed/modified.
    • For proteins directed to lysosomes, mannose-6-phosphate (M6P) is attached.

    COPII Vesicle Formation

    • COPII proteins bind to a specific cytosolic sequence of proteins embedded in the ER membrane.
    • They collect proteins into clusters with attached luminal proteins, which are then pinched off as small COPII vesicles.
    • COPII vesicles move along microtubules to the cis Golgi, shedding their coat on the way.

    Organelle Fusion

    • SNARE (SNAP receptor) proteins mediate organelle fusion, drawing membranes close together.
    • COPII vesicles must fuse with cis Golgi only, making recognition important.

    COPI Vesicle Formation

    • COPI vesicles move proteins from the Golgi to the ER.
    • Luminal cargoes are recognized by a KDEL sequence, which binds to the KDEL receptor on the Golgi membrane.
    • The COPI coat assembles, and subsequent events occur in reverse as the COPII vesicle mechanism.

    Protein Trafficking from the Golgi

    • Soluble proteins destined for lysosomes are recognized by the M6P modification acquired in the Golgi.
    • They bind to the M6P receptor, which recognizes M6P at the luminal surface.
    • They have short sequences that allow assembly of a clathrin coat at the cytosolic surface.
    • Coated vesicles punch off from the Golgi, are transported, uncoated, and recognized by late endosomes, which they fuse with.

    Lysosomal Functions

    • Low pH causes the cargo to dissociate from the M6P receptor, which is transported back to the trans-Golgi.
    • The cargo proceeds to a lysosome, where enzymes degrade imported materials and recycle macromolecules.
    • Genetic differences in these enzymes underlie a variety of lysosomal storage diseases (LSDs).

    Enzyme Replacement Therapy

    • Imperfect targeting of M6P receptors allows some to escape to the plasma membrane, where they can be recovered to lysosomes by endocytosis.
    • Administration of M6P-modified forms of missing enzymes in Gaucher disease results in the enzyme being endocytosed by the M6P receptor and delivered to lysosomes.

    LDL Receptor Trafficking

    • All cells express low-density lipoprotein (LDL) receptors, which bind to the ApoB-100 component of LDL.
    • The cytosolic domain of the LDL receptor has sequences that interact with AP2 and thereby clathrin, which assembles LDL receptors and cargo into clathrin-coated pits for trafficking to endosomes.
    • In the acidic lumen of endosomes, LDL dissociates from its receptor.

    Ion Channels

    • Ion channels open and close quickly, in less than 1 ms, and can allow several million ions to pass through.
    • They mediate the fastest communication in the cell.

    Regulation of Intracellular Activities

    • Membrane potential changes are transduced as a messenger that enters the cell, typically calcium, through the opening of voltage-gated calcium channels (VGCaCs).
    • VGNa/KCs are analogous to cables, while VGCaCs are analogous to the appliance, and VGICs are important therapeutic targets.

    Nicotinic Acetylcholine Receptors

    • Nicotinic acetylcholine receptors, found in muscle, respond to acetylcholine (ACh) released from pre-synaptic fibers.
    • Drugs interacting with these receptors can relax muscle (during surgery) and treat myasthenia gravis (an autoimmune condition).

    GABA/Glycine Receptors

    • GABA/glycine receptors, which are chloride permeable, mediate most synaptic transmission in the CNS.
    • Drugs targeted to these receptors are used to relieve anxiety and as general anesthetics.

    Voltage-Gated Cation Channels

    • Voltage-gated cation channels consist of 24 membrane spanning regions (4 × 6) arranged around a central pore.
    • For Na+ and Ca2+ channels, the entire channel is comprised of a single protein chain.
    • For K+ channels, four protein chains, each with six membrane-spanning domains, are required.

    Ion Selectivity

    • Ion selectivity arises from a narrow selectivity filter, where cations pass through single file, and surrounding amino acid residues interact.
    • The selectivity filter of Ca2+ channels has two Ca2+ binding sites, which can bind Ca2+ selectively and tightly, allowing selectivity.

    Channel Gating

    • In closed channels, the residues at the tip of TMD6 come together to form a tepee shape, occluding the channel.
    • The voltage sensor consists of four positively charged residues on TMD4, which move outwards in the plane of the membrane when the PM depolarizes.
    • This movement pulls a short cytosolic helix linking TMD4-5, which links the voltage-sensor to TMDs forming the pore, leading to twisting of pore-lining helices and opening of the channel.

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    Description

    Learn about the role of Rab proteins in trafficking from the endoplasmic reticulum, their activation and inactivation, and their recognition by other organelles. Understand how Rab-GTP and Rab-GDP facilitate vesicle trafficking.

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