Lecture 3-11: Secretory and Endocytic Pathways

Secretory and Endocytic Pathways

Overview

• Follow mechanisms responsible for the transport of proteins and molecules within cells.

• Key players include the endoplasmic reticulum (ER), Golgi apparatus, lysosomes, and various membranes.

SNARE Proteins

• SNAREs: Soluble N-ethylmaleimide-sensitive factor Activating protein REceptor, memBrand proteins facilitating vesicle fusion.

  • v-SNAREs: Found on vesicles, mediate fusion.

  • t-SNAREs: Found on target membranes.

• Vesicle docking involves the matching of SNAREs and the association of Rab proteins (a type of G protein).

• Fusion leads to delivery of proteins and the residence of SNARE complexes on target membranes.

• Recycling: SNAREs can be recycled after vesicle fusion.

Mechanism of Membrane Fusion

• Membrane fusion is driven by twisting interactions between v-SNAREs and t-SNAREs.

• Helix formation initiates locking of vesicles to target membranes.

• Membrane Proximity: Twisting action brings lipid bilayers closer until fluid dynamics cause fusion.

Endoplasmic Reticulum (ER)

• Dictates Size: The size of the ER is determined by the amount of secreted/membrane protein produced.

Protein Glycosylation in the ER

• Majority of proteins synthesized in the ER undergo glycosylation (addition of sugar molecules).

• N-glycosylation: Addition of sugars to asparagine residues, regulated by consensus sequences such as Asn-X-Ser.

• Glycan chains are trimmed and modified in the Golgi; proteins cannot exit the ER until glycosylated.

Quality Control in the ER

• Quality control prevents misfolded proteins from exiting the ER.

• Misfolded proteins bind to sensors which activate chaperones, enhancing protein-folding capacity.

ER Stress

• Accumulation of misfolded proteins can lead to ER stress, influenced by calcium levels and glycosylation inhibitors like tunicamycin.

• Misfolded proteins can lead to apoptosis if not resolved.

Golgi Apparatus

• Acts as a modification and sorting center for proteins.

• Processes proteins received from the ER; modifications include glycosylation changes.

• Structure: Stack of flattened membrane-bound spaces with distinct cis (receiving) and trans (shipping) sides.

Exocytosis

• Two types: Constitutive (continuous secretion) and Regulated (triggered by signals).

• In neurons, regulated secretion involves calcium influx which triggers neurotransmitter release.

Endocytosis

• Uptake of extracellular materials: includes phagocytosis, pinocytosis, and receptor-mediated endocytosis.

• Phagocytes (e.g., macrophages) engage in phagocytosis to engulf pathogens.

Receptor-Mediated Endocytosis

• Involves binding of receptors with extracellular substances (e.g., LDL).

• Cargo is sorted in endosomes, leading to recycling, degradation in lysosomes, or transcytosis.

Viral Mechanisms

• Viruses can exploit endocytic pathways and secretory mechanisms to enter cells and replicate.

Lysosomes

• Digestive enzymes within lysosomes break down macromolecules, requiring an acidic environment to function.

• Can digest products from phagocytosis, endocytosis, and autophagy.

Key Points Summarized

• Exocytosis involves SNARE proteins and Rab G proteins.

• The ER is involved in glycosylation and protein folding quality control.

• Golgi processes and sorts proteins post-ER.

• Endocytosis incorporates several mechanisms for material uptake.

• Lysosomal enzymes degrade ingested or internalized materials.