Lecture 5 - Cell Adhesion and Communication (part 1) Flashcards
Through what structures can connections between cells be established by?1
- tight junctions
- adherens junctions
- desmosomes
- gap junctions
- synapses
Connections between cells and the underlying matrix can be established by…
- hemidesmosomes
- focal adhesions
- non-junctional adhesions
What are the three classes of specialised cell junctions recognised by their ultra structure? And what connections are involved in these?
1- Occluding junctions tight juctions 2- Attachment junctions Adherens juntions, desmosomes, hemidesmosomes, focal adhesions 3- communiation junctions Gap junctions, synapses
What is the apical side of the cell?
The side towards the lumen
What is the basolateral membrane?
A fraction of the cell plasma membrane which faces adjacent cells and the underlying connective tissue
What is the purpose of occluding junctions? (tight junctions)
-connect neighboroughing epithelial cells
-prevent diffusion of molecules from the apical to the basolateral sides
e.g. seal apical surface of epithelial sheet in the gut
so that not transport of proteins is possible across this barrier and must use a trancellular route, option for regulation
What proteins are involved in forming tight junctions?
-Claudins
-Occludins
Tetraspanin transmembrane proteins
What do the cytoplasmic regions claudins and occludins interact with?
ZO- proteins through the PD-Z domains
e.g. ZO-1 (Zona occludins 1) an adapter proteins which also interact with the actin cytoskeleton
What are PD-Z domains?
recognised scaffolding interacting motifs
Give an example of an important tight junction in the body and what and how it regulates passage of molecules
Tight junctions between intestinal epithelial cells
Regulates the uptake of glucose
BY:
-prevents passage from the intestinal lumen through the epithelial cells to the blood
-Glucose/Na+ has to be transported through the Na+/Glucose symport protein (regulated process) through the apical membrane into the epithelial cells
-glucose can pass into the blood through the GLUT2 protein
-Na+ pass into blood through Na+/K+ ATPase protein (requires ATP hydrolysis) through basolateral membrane
Concentrations of gluose high in intestinal lumen, need to be transported
Concentrations of Na+ high in the intestinal lumen, and blood, low in epithelial cells
Concentrations of K+ high in Epithelial cells low in blood
What are CAMs and what junctions are they involved in?
Cell adhesion molecules involves in Adherens junctions
- provide tethering continuity for tissue formations
- transmembrane proteins
- interact with cytoskeletal componants via adapter proteins (orientation important)
- 5 classes
What are the 5 classes of CAMs?
Homophillic interactions
- Cadherins e.g. E cadherin
- Ig-superfamily e.g N-CAMs
Heteropihllic interactions -Mucin-like CAMs interact with -Selectins e.g. P-selectin -Integrins e.g. a3B1
What are the features of cadherins?
- wide group of cell-cell adhesion molecules
- Ca2+ required for dimerisation of cadherin monomers
- integral membrane glycoproteins 720-750 amino acids long
- bind to cadherin dimers of adjacent cells via HAV domain (Histidine, Alanine, Valine binding motif)
- binding requires Ca2+
- internal cytosolic domain attached to cytoskeleton via trio of catenins
- homophillic interactions
Give some examples of cadherins and where they are found
E-cadherin - non-neural cells
P-cadherin - placenta
N-cadherin - Neural tissue, cardiac and skeletal muscle
Why is Ca2+ needed for cadherin dimer binding?
Ca2+ allows a conformational change in the cadherin domains causing them to extend out away from the cell membrane and towards each other to bind via HAV domain
How do the cytoplasmic domains of cadherins interact with the actin cytoskeleton?
B catenin bind to the intracellular portion of the cadherin then interacts with alpha catenin which binds to the actin cytoskeleton
p120 (another adaptor and scaffolding protein) helps the aggregation process
How do cadherins form tight adherens junctions?
rows of caherins interacting with the cytoplasmic catenins encircling the exterior or interlocking adjacent cells
How are the cadherins adherens junction interactions strengthened?
- weak interactions are strengthened by clustering of the cadherin complexes and the release of IQGAP, and through the aggregation of signalling proteins
- this leads to the recruitment of adapter proteins, b catenin, a catenin and p120 protein compacting and stabilising the arrangement. p120 can then regulates Rho GTPases
- RhoGTPases are involved in the production of stress fibres (Rho),
- alpha care in is involved in the formation of filopodia (Cdc42) and lamellipodia (Rac)
What are Desmosomes?
A patchlike cadherin mediated connection between adjacent epithelial cells (interact with intermediate filaments e.g. keratin in keranocytes) , strengthen the tissues by binding cells together whilst allowing movement of molecules in the intercellular space
What are the features of desmosomes?
-specialised cell-cell junctins
-15-20nm thick
-patches of cadherins (desmoglein, desmocollin)
-interact with adapter proteins (plakoglobin, desmoplakin)
interact with intermediate filaments (e.g. keratins)
Give an example of a disease involving desmosome
Pemphigus vulgaris
- autoimmune disease
- antibodies directed against desmosomal cadherin proteins
- leads to the disruption of desmosome in keranocytes
- skin blistering, inflammatory responses, leakage of bodily fluids into epithelium
Give an example of Ig superfamily of CAMs and their features
NCAMs
- integral membrane protein encoded by a single gene
- predominant in neuronal cell-cell adhesions
- diversity is regulated by alternative splicing
- mediate homophillic interactions with NCAMs on opposing cells
- Ca2+ independent interation
What is the structure of NCAMs?
Ig loops on extracellular domain
anchored into cell membrane by transmembrane domain
To what do the following Ig superfamily CAMs bind to?
NCAM 180, 120?
PECAM?
ICAMs-1,2,3, VCAM1?
N-CAM 180/120 = N-CAMs
PECAM = PECAM or alpha-V-beta-3 integrin
ICAMs-1,2,3, V-CAM = beta-2 integrin
What three different types of N-CAMs can be produced by alternate splicing and what are their structures?
N-CAM 120: has a GPI anchor to hook into membrane, polysialic acid domain, binding site for heparan sulphate proteoglycans/other N-CAMs
N-CAM 140: has transmembrane domain, polysialic acid domain, binding site for heparan sulphate proteoglycans/other N-CAMs
N-CAM 180: (longest, cytoplasmic region longer than N-CAM 140 and w/ hooklike end)
What are N-CAM adhesive properties mediated by?
chains of sialic acid (negatively charged sugars)
-heavily sialated (e.g. embryonic tissue) form weaker interactions, possibly due to repulsion between negatively charged sialic acids. Allows cells to move or to develop tissue
Give an example of a selectin and a mucin
P-selectin
Mucin like CAMs
What are features of the interactions between selectins and mucins?
-involved in cell movement -key role in leukocyte extravasion
-heteophillic interaction
Selectins have carbohydrate binding protein domains (lectins)
-lectin domain highly conserved
-lectin binds to carbohydrate of mucin like CAM on another cell
-Ca2+ dependent interaction
-low affinity (
How does a leukocyte extavasate? (role of P-selectin)
- Inflammatory signal produced at the site of infection and causes endothelial cells to upregulate production of PAF (platelet activating factor) and P-selectin
- Oligosaccharides (mucin glycoproteins or glycolipids) on passing leukocyte binds to p-selectin, trapping the leukocyte, and permitting a rolling movement along the endothelial cells because of the weak attachement
- When leukocyte reaches the site of infection the PAF receptor binds to the inflammation induced PAF on endothelial cells
- This interaction activates integrins (alpha-L-beta-2 integrin) on the leukocyte causing leukocyto to roll over and bind to intracellular adhesion molecules e.g. ICAM = B2 integrin, allowing a physical interaction so that cells can extravaste into the infected tissue
