Cell Junctions and Adhesions

Question 1

Tight Junctions

Answer 1

1. Function
   
   1. Cell to Cell anchorage
   2. Stitch two apical parts of membrane together
2. Transmembrane proteins
   
   1. Occludins and Claudins
      
      1. 4 membrane pass transmembrane proteins with two tiny extracellular loops
      2. Form adhesions with corresponding occludins and claudins in adjacent membrane
      3. Tiny extracellular loops bring two membranes close together to form sealing strands
3. Cytoskeleton
   
   1. Actin
      
      1. On cytoplasmic side, occludins and claudins interact with adaptor proteins such as ZO-1 which attach them to actin cytoskeleton

Question 2

Belt desmosomes

Answer 2

1. Function
   
   1. Cell to Cell anchorage
   2. Help cells-cell interaction by binding lateral membrane of adjacent cells together through formation of a belt of cadherins
   3. Give cell polarity (belt desmosomes influence formation of tight junctions, therefore belt desmosomes are needed for cell polarity)
   4. Cell adhesion keeps cell stationary
2. Transmembrane proteins are cadherins
   
   1. Cadherins are Ca2+ dependent adhesion proteins with 4 extracellular domains that bind to Ca2+
   2. For cadherin mediated cell adhesion to form, they have to form cis homophilic dimer that allows cadherins to interact with each other on the same cell first
   3. Cadherins then form trans-homophilic interactions so cadherin dimers on one cell interact with cadherin dimers on opposite cell.
   4. This binding of cadherins forms a belt-like structure in the lateral membrane that binds adjacent cells to another
   5. Cadherins always find same type of cadherin so they can self-organize into same tissue type.
      
      1. Epithelial: E-Cad
      2. Neurons: N-Cad
   6. NOTE: Engagement of E-Cadherins via cis-homophlic interactions to form belt desmosomes is required before formation of tight junctions.
3. Cytoskeleton
   
   1. Actin
      
      1. On intracellular side, the cadherins have short cytoplasmic tail that binds alpha/beta catenins and gamma plakoglobbin) that then attaches the cadherins to actin cytoskeleton

Question 3

Spot desmosomes

Answer 3

1. Aka macula adherens
2. Function
   
   1. Cell to Cell anchorage
   2. Rivets speckled all over lateral cell membrane hold adjacent cells together
   3. Provide mechanical strength needed to hold tissue together.
3. Transmembrane proteins
   
   1. Cadherins- Desmocollins and desmoglein
4. Cytoskeleton
   
   1. Intermediate filaments
      
      1. On cytoplasmic side desmocollins and desmogleins bind to plakoglobin, desmoplakin, and plakophilin which then interact with intermediate filament

Question 4

Hemidesmosomes

Answer 4

1. Function
   
   1. Help anchor cell to ECM
2. Transmembrane proteins
   
   1. Integrin alpha6 beta4 involved
      
      1. Transmembrane proteins that have alpha and beta subunit
   2. Bind to collagen and other ECM elements in the extracellular side
3. Cytoskeleton
   
   1. Bind to various cytoplasmic plaques that link them to keratin intermediate filaments
   2. They are responsible for providing mechanical strength to hold cells down to basement membrane

Question 5

Focal Adhesions

Answer 5

1. Function
   
   1. Help anchor cell to ECM
   2. Not visible under EM
2. Transmembrane protein
   
   1. Integrins
      
      1. Have an alpha and beta subunit
      2. Bind to extracellular matrix proteins like fibronectin, laminin, collagen using their RGD (Arginine, Glycine, Glutamate) recognition motif
3. Cytoskeleton
   
   1. In the cytoplasmic side, they bind to adaptor proteins such as talin and vinculin and alpha-actinin to attach themselves to actin cytoskeleton

Question 6

Gap Junctions

Answer 6

1. Function
   
   1. Cell to Cell communication
2. Transmembrane protein
   
   1. Connexin
      
      1. 4 pass transmembrane protein
      2. Have two tiny extracellular loops that allow them to interact with connexon molecules in opposite membrane in order to form direct channel between two cell membranes
   2. Connexon channel
      
      1. Formed from a hexamer of Connexins
      2. Extracellular loops of one connexon in membrane 1 bind to extracellular loop of second connexon in membrane 2
      3. Can change conformation to open or close. This conformational change is regulated by Ca2+, voltage, pH etc.
3. Cytoplasmic side
   
   1. NOT attached to cytoskeleton

Question 7

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Answer 7

1. Mutation in Claudin 16
2. Autosomal recessive renal disorder
3. Symptoms
   
   1. Leaky tight junctions in kidney disrupt Mg and Ca balance in blood and kidneys
   2. Low Mg in blood
   3. High Ca in Urea

Question 8

Hypotriosis with Juveline Macular Dystrophy

Answer 8

1. Mutation in P-Cadherin
2. Symptoms
   
   1. P-Cadherins are expressed in retina and hair follicles
   2. Results in progressive retinal degeneration leading to blindness

Question 9

Deafness

Answer 9

1. Caused my multiple mutations in gap junctions

Question 10

Blistering diseases

Answer 10

1. People have blisters all over body constantly
2. Autoimmune disease
   
   1. Antibodies attack components of spot or hemidesmosomes so that junctions fall apart and you get a blister

Question 11

Pemphigus Folliaceous

Answer 11

1. Immune system produces antibodies against desmoglein
2. Spot desmosomes are disrupted
3. Epidermal layer is split in the middle between cells
   
   1. This is because spot desmosomes hold epithelial cells together

Question 12

Pemphigoid

Answer 12

1. Immune system produces antibodies against components of hemidesmosomes
2. Epidermal layer is separated from underlying basement membrane
   
   1. This is because hemidesmosomes hold the cell to the basement membrane

Question 13

Non-junctional adhesion mechanisms

Answer 13

Needed for:

1. Leukocyte (neutro, baso, eosinophils) extravasation during inflamamtory response
   
   1. Selectins
   2. Immunoglobulin superfamily
2. Wound healing
3. Cancer metastasis

Question 14

Selectins

Answer 14

1. Have extracellular Ca2+ binding sites
2. On top of extracellular domain, you have carbohydrate recognition motifs that recognize glycoproteins or glycolipids on surface of other cells
3. Form a single pass transmembrane protein

Question 15

IgCAM

Answer 15

1. Single pass transmembrane protein
2. Have extracellular Immunoglobbulin domains
3. Are called ICAMs and VCAMs

Question 16

Process of Leukocyte Extravasation

Answer 16

1. Endothelial cell
   
   1. Phase 1: expresses P-selectin
   2. Phase 2: expresses ICAM and VCAM
2. Leukocytes
   
   1. Phase 1: have glycoproteins
   2. Phase 2: express integrins
3. Process
   
   1. A cut in skin occurs
   2. Bacteria gets in
   3. Resident macrophages attempt to fight off bacteria and release cytokines to recruit leukocytes
   4. Endothelial cell expresses P-selectins which bind to glycoproteins on leukocyte cell membrane slowing them down in the blood so that they begin rolling
   5. Rolling leukocytes express integrin on cell surface while endothelial cell begins expressing ICAMs and VCAMs
   6. Integrins on leukocytes bind to ICAMs and VCAMs on endothelial cell causing leukocytes to come to a complete stop
   7. Once leukocytes stop, they change morphology, extend lamellipodia, and squeeze through endothelial cell surface to fight bacteria.