L39: The secretory pathway

• What is the biosynthetic/secretory pathway in eukaryotic cells?

  It involves vesicular transport of proteins
• What percentage of human proteins are secreted?

  15%
• What are the main functions of the endoplasmic reticulum (ER)?

  Lipid synthesis and protein translocation
• What happens to proteins that fail to fold or assemble in the ER?

  They get degraded
• How can protein translocation occur?

  Co-translational or post-translational
• What is the role of the N-terminal signal sequence in secretory proteins?

  It targets them to the ER surface
• What is Sec61?

  A core component of the eukaryotic translocator
• What is the function of the Signal Recognition Particle (SRP)?

  It docks ribosomes on the ER membrane
• What is the appearance of the rough ER due to?

  Ribosomes docking on its membrane
• How does Sec61 function in protein translocation?

  It opens for proteins with an ER import signal
• What role do chaperones play in the ER?

  They detect protein misfolding and keep the misfolding proteins from aggregating and entering the secretory pathway
• What percentage of proteins are glycosylated in the ER?

  50%
• What is the significance of N-glycosylation?

  It aids in proper protein folding
• What happens to incompletely folded proteins in the ER?

  They get another chance to fold
• What is the role of the Golgi complex?

  Protein packaging and sorting
• What is the structure of the Golgi complex?

  A stack of flattened membrane-enclosed sacs
• How are lysosomal enzymes modified in the Golgi?

  They receive mannose 6-phosphate signals
• What is the function of M6P receptors?

  They recognize M6P signals in lysosomal enzymes
• What happens to clathrin-coated vesicles after budding?

  They become uncoated for fusion
• What is the pH of late endosomes?

  5.5
• What is the consequence of mutations in lysosomal sorting signals?

  They lead to lysosomal storage diseases
• What is Gaucher's disease caused by?

  Lack of glucocerebrosidase
• What is Tay Sachs disease associated with?

  Insufficient hexosaminidase A
• What is the role of the N-acetylglucosamine phosphotransferase?

  It adds N-acetylglucosamine phosphate to hydrolases
• What happens if the signal patch is mutated?

  Proteins won't acquire M6P signals
• What are the key steps in the secretory pathway?

  1. Protein translocation into the ER
  2. N-glycosylation in the ER
  3. Protein folding and quality control
  4. Transport from ER to Golgi
  5. Sorting and modification in the Golgi
  6. Delivery to lysosomes or secretion
• What are the consequences of defects in lysosomal sorting?

  • Accumulation of undigested materials
  • Development of lysosomal storage diseases
  • Impaired degradation of cellular components
• What are the characteristics of lysosomal enzymes?

  • Hydrolytic enzymes
  • Work best at pH 5.0
  • Include proteases, nucleases, glycosidases
• What is the role of clathrin in vesicular transport?

  • Forms cages around vesicles
  • Facilitates vesicle budding
  • Involved in transport to lysosomes
• What is the significance of M6P in lysosomal enzyme targeting?

  • Acts as a targeting signal
  • Recognized by M6P receptors
  • Ensures proper sorting to lysosomes
• What is the role of chaperones in the ER?

  • Assist in protein folding
  • Prevent aggregation of misfolded proteins
  • Regulate disulfide bond formation
• What is the process of N-glycosylation in the ER?

  • Addition of complex oligosaccharides
  • Occurs on Asparagine residues
  • Important for protein folding and stability
• What are the types of protein translocation?

  • Co-translational translocation
  • Post-translational translocation
• What is the role of the ER in protein synthesis?

  • Site for protein translocation
  • Involved in lipid synthesis
  • Quality control for protein folding
• What are the main components of the secretory pathway?

  • ER
  • Golgi complex
  • Lysosomes
  • Vesicles
• What are lysosomal storage diseases?

  • Genetic disorders due to enzyme deficiencies
  • Result in accumulation of undigested materials
  • Examples include Gaucher's and Tay Sachs diseases
• How does protein translocation occur?

  • Thru a translocation pore
  • Proteins acquire their native structure (thru folding and assembly)
  • Proteins are N- glycosylated (the ER adds complex oligosaccharides onto certain amino acids)
• Sec 61:

  • It is a sequence-gated aqueous channel
  • Has a 'plug' that allows it to be in a closed state
  • It is closed unless activity used to avoid diffusion of small molecules
  • It opens for proteins containing an ER import signal sequence
• Lysosomal hydrolases M6P modification

  1. Lysosomal hydrolases signal patch is recognised by the N-acteylglucosamine phosophotransferase through its recognition site.
  2. The catalytic site adds N-acteylglucosamine phosphate.
  3. A second enzyme removes the N-acteylglucosamine leaving the M6P group.