BCH3021 Lecture Notes - Lecture 15: Secretion, Secretory Protein, Fusion Protein
Lecture 15 – The Secretory and Endocytic Pathways: Organelles and Molecular
Mechanisms of Protein Trafficking
Why this is studied:
• Biological: 60+ human diseases associated with defects in these pathways that
affect organelles
• Global market for protein drugs: >US $234 billion in 2014
• 70% synthesized/secreted from eukaryotic cells
Functions, relationships and formation (biogenesis) of organelles
Protein synthesis and trafficking routes
Moving proteins around the secretory and endocytic pathways: machinery and
mechanisms
• Signal sequences used to direct specific proteins to organelles
• Transfer of proteins between organelles involving budding and fusion of
transport vesicles
Structure and Biogenesis of Endoplasmic Reticulum (ER) and Golgi Complex
• ER large network of membrane bound tubes involved in protein and lipid
synthesis, calcium storage and detoxification
• Golgi is dynamic organelle that accepts cargo from ER, modifies and passes it
further along secretory pathway
o Contains three distinct membrane bound compartments → further
modify proteins as they pass through
• When cell divides, has to pass intact organelles or template onto
daughter cells
• ER remains intact and functional during mitosis and is split among
daughter cells
• Golgi breaks down during mitosis and reforms from ER
Endoplasmic Reticulum (ER)
• First organelle in secretory pathway
• A membrane-bound reticular organelle organized into two
functional domains
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• Network of interconnected membrane tubules enclosing single
internal space (lumen or cisternal space)
o Outside of tube faces cytosol
o Lumen is topologically equivalent to exterior of cell,
same pH
• Occupies ~10% of cell’s volume
• ER membrane comprises over half membrane in cell
o Is continuous with outer nucleus membrane
• Central role in lipid and protein biosynthesis (1/3 of cell’s
protein is made in ER)
• Functions
o Protein synthesis, modification, trafficking
▪ Synthesis of glycosylation of proteins
▪ Synthesis of resident proteins of secretory/endocytic organelles
▪ Proteins can be soluble
o Membrane synthesis
▪ Site of synthesis of lipids incorporated into membranes of most
of organelles in cell
o Calcium storage
▪ Ca2+ stored for release in response to extracellular signals
o Detoxification
▪ ER resident enzymes detoixify lipid soluble drugs and toxic
metabolites
• Comprised of two parts: Rough ER and smooth ER
o Rough and smooth ER structures can be separated by cell fractionation
procedures
▪ If cells are disrupted by homogenization to ER fragments and
reseals into small vesicles – microsomes
o Rough: contains ribosomes 13 mins involved in secretory protein
synthesis
▪ Synthesis of cytosolic, nuclear, mitochondrial and peroxisomal
proteins occurs in cytoplasm on free ribosomes
▪ Synthesis of secretory proteins occurs on ribosomes bound to
membrane of ER
▪ Messenger RNA is translated by ribosome
o Smooth: region of ER that lacks ribosomes
▪ Site of lipid synthesis, Ca2+ storage and detoxifying enzymes
• Calcium is pumped in by a specific ATP-dependent
pump
• Ca2+ released from smooth ER through IP3-gated
channels or ryanodine receptors
• ER synthesizes most lipids including phospholipids and
cholesterol
• Major phospholipid is phosphatidylcholine
o Synthesis occurs exclusively on cytoplasmic
leaflet of ER membrane
• Scramblase: protein that moves phospholipids from
cytoplasmic leaflet to luminal leaflet of ER membrane
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