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What cellular structure is required to form tissues from individual cells by connecting cells to other cells and to the ECM?
What are the three functional groups of cell junctions?
- 1. Anchoring junctions - mechanically attach cells to other cells or the ECM
- 2. Occluding junctions - seal the contacts between cells
- 3. Channel-forming/communicating junctions - allow chemical or electrical signals to pass from one cell to another.
What are the basic units of a cell junction?
- 1. Transmembrane adhesion protein - spans the cell membrane and connects the inside and outside environment of the cell
- 2. Adaptor protein - allows recruitment of additional components to the adhesion complex and regulates the adhesion complex
- 3. Cytoskeletal linkers - physical link between the adhesion complex and the cytoskeleton
How are adhesion proteins classified?
Classified by the number of times they cross the membrane ie. single pass, two pass, three pass, etc.
Name the four types of cell-cell adhesion complexes.
- 1. Tight Junctions (Occluding Junctions)
- 2. Zonula Adherens aka adherens junctions (Anchoring Junctions)
- 3. Desmosomes (Anchoring Junctions)
- 4. Gap junctions (Channel-forming Junctions)
How do cell junctions increase the stability and strength of the small junctions relative to the large size of the cell?
- made up of large protein complexes
- 'Clustering' of the transmembrane adhesion proteins in the plasmamembrane - the combined strength of multiple bond interactions increases overall strength of the junction
- The clustered adhesion proteins link to cytoskeletal network which produces a huge tension-bearing protein interaction network running through the tissue
What is 'freeze fracture' electron microscopy?
- A technique used to look at membranes that reveal the pattern of integral membrane proteins.
- Casts are made of frozen membrane surfaces
Where can tight junctions be found in the cell?
- zonula= a belt that goes all around the cell
- located very near the apical domain; join neighboring cells closely
Describe the structure of tight junctions.
- Formed by strands of interacting transmembrane proteins observable by freeze-fracture electron microscopy.
- Specifically, tight junctions are formed by the transmembrane adhesion proteins Claudin and Occludin binding to the same type of molecule on neighbouring cells (i.e. ClaudinClaudin or Occludin-Occludin interactions).
What is the primary function of a tight junction?
Controls solute diffusion between cells (lateral diffusion)
What is the structure of a claudin?
- 4 pass transmembrane protein
- essential for tight junction formation
What is the structure of an occludin?
- 4 pass transmembrane receptor
- required for barrier function
- not needed for maintaining overall tight junction structure
How can the permeability of the barrier across the epithelium be tested?
Barrier permeability can be tested by using a dye/tracer that is added to either the apical or basal side of the epithelium and observing whether the dye/tracer diffuses over the junction
Give an example of the clinical relevance of tight junctions.
Loss of tight junction claudin 16 disrupts clearing of electrolytes from blood- leads to calcified deposits in the kidney and kidney failure.
Describe the structure of an adherens junction.
- Form a continuous adhesion belts that completely cover the circumference of the cell on the lateral domain just basal to tight junctions
- Critical in epithelia for the formation of 2D sheets of cells
- Composed of single pass transmembrane proteins called classical cadherins
- link to the actin cytoskeleton
Explain how cadherins cluster.
- 1. Calcium binding to cadherin causes cadherin's extracellular domain to straighten and form "cis-homodimers" on the same cell.
- 2. Cadherin straightening promotes "trans" homodimerization, which means that a cadherin cis-homodimer on one cell binds another cadherin cis-homodimer located on the surface of another cell.
- 3. This trans-bound complexes cluster together in the plane of the membrane
- Cadherins link to the actin cytoskeleton via intracellular anchoring complex containing adapter proteins called "catenins".
Provide an example of the clinical relevance of adherens junctions.
Loss of cadherin causes some cancers. Loss of classical cadherin is associated with loss of epithelial structure which is a hallmark of cancer.
Describe the structure of desmosomes (macula adherens).
- based on adhesion between cadherin-like receptors: Dsc (Desmocollin) and Dsg (Desmoglein)
- Bind the keratin family of intermediate filaments
- small spotlike-junctions that form along the entire lateral domain of cell types in tissues that are exposed to tensile forces/mechanical stress like skin
- maintan the orientation of cytoskeletal elements between cells
Provide an example of the clinical relevance of desmosomes.
loss of Dsg cause Pemphigus vulgaris- loss of adhesion between layers of the skin results in skin blistering
What is the major function of gap junctions?
- allow communication and sharing of nutrients between cells
- important in both epithelial and non-epithelial cells ie. cardiac myocytes
- also involved in hearing
Describe the structure of gap junctions.
Connexin are the gap junction adhesion proteins. Six connexin form a hexamer called a connexon in the lateral membrane domain of one cell membrane. A connexon will then bind a similar hexamer/connexon in the lateral membrane domain of a neighbouring cell to form a functional channel that can be regulated (ie. can be opened or closed) and can pass small molecules between linked cells in the epithelium
Provide an example of the clinical relevance of gap junctions.
Loss of connexin 26 causes Vohwinkel syndrome (keratodema)