3rd lt

• Endomembrane system


  Made up of a network of membranes
• Traffic in the Cell

  1. Materials shuttled between organelles from the Golgi complex to the plasma membrane

  2. Highly organized

  3. Membrane-bound transport vesicles bud off from the donor membrane compartment

  4. Transport vesicles move through the cytoplasm in a directed manner pulled by motor proteins
• Transport vesicles

  • Derived from a specific cell compartment
  • Pulled by the motor proteins through the cytoskeleton; like a train (transport vesicle) moving along a railroad track (motor proteins)
• Distinct Pathways


  • Biosynthetic pathway
  • Secretory pathway
  • Endocytic pathway
• Biosynthetic pathway


  Proteins synthesized in the ER are modified during passage through the Golgi complex and transported from the Golgi to various destinations

  
• Secretory pathway


  Proteins synthesized in the endoplasmic reticulum are destined to be discharged (secreted) from the cell
• Types of Secretory Activities

  • Constitutive secretion
  • Regulated secretion
• Constitutive secretion


  Materials transported in secretory vesicles from sites of synthesis and discharged into extracellular space in a continual manner
• Regulated secretion


  Materials stored as membrane-bound packages and discharged only in response to an appropriate stimulus
• Regulated secretion


  • Endocrine cells release hormones
  • Pancreatic acinar cells release digestive enzymes
  • Nerve cells release neurotransmitters
• Secretory granules


  Large, densely packed, membrane-bound packages that store materials to be secreted
• Endocytic pathway


  Movement of materials from outer surface of cell to compartments such as endosomes and lysosomes within the cytoplasm

  
• Types of Cargo


  • Secreted proteins
  • Lysosomal enzymes
  • Membrane proteins
• Sorting signals


  Amino acid sequences attached to transport vesicles that route them to the appropriate cellular destinations
• Autoradiography


  Use of radioactive materials to trace the movement of molecules
• Green Fluorescent Protein (GFP)


  Utilizes a gene from jellyfish that encodes a small protein which emits green fluorescent light
• Types of Receptors


  • Housekeeping Receptors
  • Signaling Receptors
• Housekeeping Receptors


  Responsible for the uptake of materials that will be used by the cell
• Housekeeping Receptors


  • Transferrin receptors
  • LDL (low-density lipoprotein) receptors
• Signaling Receptors


  Responsible for binding extracellular ligands that carry messages that change the activities of the cell
• Receptor down-regulation


  Process of the destruction of the receptor, reducing the sensitivity of the cell to further stimulation by the hormone or growth factor
• Ubiquitin


  Protein "tag" that is added enzymatically to the cytoplasmic tail of signaling receptors, marking them for endocytosis and destruction
• Endosomes


  Dynamic network of tubules and vesicles that represent distribution centers along the endocytic pathway

  
• Endosome types

  • Early endosomes
  • Late endosomes
• ESCRT complexes


  Protein complexes that sort ubiquitinated receptors into a cluster within the late endosomal membrane, cause the membrane to invaginate, and sever the neck of the invagination to release the newly formed intraluminal vesicle
• Late endosomes/Multivesicular bodies (MVBs)


  Endosomes containing internal vesicles where signaling receptors are segregated
• Receptor-mediated endocytosis


  1. Receptors are transported in vesicles to early endosomes, which serve as sorting stations

  2. Receptors are concentrated into specialized tubular compartments of early endosomes as recycling centers

  3. Released ligands become concentrated in a sorting compartment before being dispatched to a late endosome and to a lysosome

  
• LDL (low-density lipoprotein)


  Cholesterol-transporting agent in the blood, with a central core of cholesterol molecules esterified to long-chain fatty acids and surrounded by a single layer of phospholipids containing apolipoprotein B-100
• LDL receptors


  Concentrated on the cell surface to take up blood-borne LDL particles
• LDL uptake

  1. LDL particles bind to coated pits, which invaginate to form coated vesicles

  2. Clathrin coat is disassembled

  3. LDL receptors pass through early endosomes and back to the plasma membrane

  4. LDL particles are delivered to late endosomes and lysosomes, where the protein is degraded and the cholesterol is used by the cell
• Niemann-Pick type C disease


  Rare inherited disorder caused by lack of a protein required to transfer cholesterol out of lysosomes, leading to cholesterol accumulation and nerve degradation
• Atherosclerosis

  Condition characterized by the formation of plaques in the inner lining of arteries, reducing blood flow and acting as sites for blood clot formation
• Statins


  Drugs that block HMG CoA reductase, a key enzyme in the synthesis of cholesterol, lowering blood LDL levels and reducing the risk of heart attack
• HDL (high-density lipoprotein)


  Cholesterol-transporting agent in the blood, with a different protein (apolipoprotein A-I) and a role in carrying cholesterol from the body's cells to the liver for excretion
• High blood levels of LDL


  Increased risk of heart disease
• High blood levels of HDL


  Decreased risk of heart disease
• CETP (cholesteryl ester transfer protein)


  Enzyme that transfers cholesterol molecules from HDL to other lipoprotein particles, tending to lower HDL cholesterol levels
• PCSK9


  Proteolytic enzyme that destroys LDL receptors in the liver, and inhibitors of which are promising cholesterol-lowering drug targets
• Rough ER (RER)


  Network of flattened sacs (cisternae) where polypeptides synthesized on ribosomes attached to the cytosolic surface are secreted proteins, integral membrane proteins, or soluble proteins that reside within compartments of the endomembrane system
• Smooth ER (SER)


  Synthesizes steroid hormones, detoxifies organic compounds, and sequesters calcium ions within the cytoplasm