19: Cell Junctions and the Extracellular Matrix Flashcards
(29 cards)
What are the two basic kinds of transmembrane adhesion proteins?
Cadherin: cell-cell
- Link to actin -> adherens junctions
- Link to IF -> desmosomes
Integrin: cell to matrix
- Link to actin -> actin-linked cell-matrix junctions
- Link to IFs -> hemidesmosomes
With do cadherins bind with strong affinity?
Velcro-principle:
Bind to their (homophilic) partners with low affinity, but many weak bonds in parallel create a strong attachment.
Can be easily disassembled by separating the molecules sequentially.
Which cadherin type is lost during epithelial to mesenchymal transition (EMT)?
E-type: epithelial cadherin
EMT occurs during
• normal embryonic development
• tissue repair and regeneration
Feature of invading and metastatic cancers
Which adaptor proteins does the linkage of cadherins to the actin cytoskeleton depend on? Briefly describe the process
Inactive binding on cytosolic side via different catenins.
Process steps:
1. membrane protrusions initiate cell-cell contact. Activation of GTPase Rac (actin regulator)
2. Rac activity => actin and cadherin recruitment expands junction
3. Rac replaced by GTPase Rho => Actin remodeling (to linear) and myosin recruitment expands the adherens junction.
Pulling on a junction in one cell will increase the contractile force generated in the opposite cell.
What are desmosomes?
Interactions between the intermediate filaments of adjacent cells.
Function: provide mechanical strength.
Abundant in tissues that are subject to high mechanical stress ex. heart muscle, epidermis
Type of IF depends on the cell type (ex. keratins in epithelial cells)
What are tight junctions? What are the transmembrane homophilic adhesion proteins involved?
Seal gaps between adjacent cells, so molecules from basal lamina/medium above cannot leak across the sheet.
Have different characteristics regarding low molecular weight permissiveness.
Allow paracellular transport: transient modification of
tight junctions to modify the flow of AAs, etc.
Claudins - important for formation and function.
Occludins - limit junctional permeability
How do tight junctions hinder transcellular transport?
Transcellular transport: TJs act as seals and fences =>
Must have specialized transporters on the apical and basolateral sides of the cells to enable movement of substances from the lumen into the ECM
What are gap junctions?
Channels connecting neighboring cells.
Spanned by connexins (vertebrates) and innexins (invertebrates).
Connexin = 4 transmemb. domains.
Six connexins form a connexon (hemichannel). Does not need to be homotypic.
Connection between connexons on adjacent cells => continuous channel.
Combinations of connexons give different properties.
Not always open. Stimuli by voltage, memb. potential, pH, [Ca2+]…
Chemical coupling: Passage of inorganic ions and water-soluble molecules, not macromolecules.
Electrical coupling: flow of ions carrying electric charge
Can you describe plasmodesmata?
Intracellular junctions between plant cells.
Desmotubules (cylindrical structure) run through the middle. Continuous with the smooth ER in the two cells, enabling lipid transfer.
Transports molecules of approx. the same size as gap junctions. Transport is regulated.
Can be removed when they are no longer required an inserted de novo.
What is the role of selectins?
Calcium-dependent (C-type) lectin (cell-surface carbohydrate-binding protein) that mediates cell-cell interactions in the bloodstream.
L-selectin: on white blood cells
P-selectin: on platelet
E-selectin: on activated endothelial cells
Can you describe the correlation between integrins and the immunoglobulin (Ig) superfamily?
Integrins bind to specific Ig-family proteins.
- ICAMs: intracellular cell adhesion molecules.
- VCAMs: vascular cell adhesion molecules.
- Heterophillic interactions: ICAM and VCAM
- Homophilic interactions: NCAM (N, neural)
Integrins = Ca2+ dependent Ig = Ca2+ independent
What three major macromolecules are the ECM constructed from?
Glycosaminoglycans (GAGs) - gel, migration, differentiation ++
- Large and highly charged polysaccharides that are usually covalently linked to protein in the form of proteoglycans.
Fibrous proteins - strength, organization
- Primary collagens
Glycoproteins - resilience
- Has asparagine-linked (N-linked) oligosaggharides.
What is the gel-like “ground substance” of the ECM?
Highly hydrated, usually formed by proteoglycans, in which collagens and glycoproteins are embedded.
Resists compressive forces on the matrix, while permitting rapid diffusion of nutrients, metabolites, and hormones.
Describe the structure of a glycosaminoglycan (GAG).
Can you name the four main groups?
Unbranched polysaccharide chains consisting of repeating disaccharide units containing one amino sugar (often sulfated) and usually a uronic acid.
Too stiff to fold, highly hydrophilic and negatively charged→ attract osmotically active Na+ ions → attract water into the matrix
Groups distinguished by sugars, linkage types, number and location of sulfate groups:
- Hyaluronan
- Chondroitin/dermatan sulfate
- Heparan sulfate
- Keratan sulfate
Can you briefly describe proteoglycan synthesis?
Core protein component synthesized by membrane
bound ribosomes in ER -> Golgi
Addition of tetra-saccharide linker (primer)
Addition of polysaccharides by glycosyl transferases
in the Golgi, covalent modifications
How does hyaluronan (hyaluronic acid) differ from the other types of glycosaminoglycans?
Has no sulfated sugars
All its disaccharide units are identical
Enormous chain length
Generally not linked covalently to any core protein.
Produced by enzyme complex at cell memb. surface
Insulates from compressive force and can force shape change during embryogenesis
What are the main differences between glycoproteins and proteoglycans?
The proteins of proteoglycan are bound to polysaccharides with amino sugars.
Glycoproteins are often short and branched, proteoglycans are often long and unbranched with a larger carbohydrate percentage by weight.
Can you characterize the collagens?
Major protein component of ECM.
Fibrous protein.
Long & stiff- triple-stranded α helical structure
Proline and glycine rich.
Often glycosylated
Can assemble into higher-order structures- fibrils (fibrillar collagens).
Fibrils are organised differently in different tissues.
Help ECM withstand tensile forces.
How are collagen fibrils organized?
Keyword: fibril-associated collagens
Cells can regulate the disposition of the collagen molecules after secretion by guiding collagen fibril formation near the plasma memb.
Fibronectin (matrix glycoprotein) helps guide.
FACs mediate the interactions of collagen fibrils with one another and with other matrix macromolecules to help determine the organization. Bind to fibril surfaces. FACs are more flexible and do not aggregate with themselves.
Can you describe elastin and its function?
Gives resilience to recoil after transient stretch.
Rich in proline and glycine, but not glycosylated.
Elastin core is surrounded by microfibrils => scaffold for elastin deposition.
Highly cross-linked to other elastin molecules, generating a network.
- Relaxed: random-coil conformation
- Stretched
Dominant ECM protein in arteries.
What are the advantages with ECM proteins containing multiple binding sites? E.g., for matrix macromolecules and for cell surface receptors
Organizes the matrix and helps cells to attach to it.
Some also have binding sites for soluble growth factors
What are the structure and functions of fibronectin?
Dimer consisting of two monomers cross-linked via disulfide bonds at their C-termini.
Exist in soluble form, and as insoluble fibronectin fibrils in the ECM (dimers are linked together via disulfide bonds). Can only assemble into fibrils on cell surfaces with fn.-binding proteins e.g., integrins.
Mediates cell-matrix interactions through different
domains. Binding to collagen, proteoglycans, integrins.
RGD peptide and synergy sequence are important for
integrin (has RGD receptors) binding
What is the basal lamina and how is it structured?
Specialized type of ECM underpinning all epithelia and surrounding individual muscle cells, fat cells, and Schwann cells. Forms mechanical connection between these cells and the surrounding connective tissue.
Thin (40-120 nm), tough and flexible.
Synthesized by the cells on either side of it.
Precise composition varies between tissues/regions.
Typically contains the glycoproteins laminin, type IV collagen, and nidogen + proteoglycan perlecan. Some have fibronectin and type XVIII collagen.
Laminin - primary organizer of sheet structure. Self-assembles guided by interactions with integrins and proteoglycans. Different isoforms.
Type IV collagen - flexible, provides tensile strength.
Laminin and type IV collagen interact with other basal lamina components. Cell-surface receptors (e.g., integrins, dystroglycan) organize basal lamina assembly.
What are the functions of the basal lamina/basement membrane?
Determine cell polarity
Influence cell metabolism
Organize the proteins in adjacent plasma membranes Promote cell survival, proliferation, or differentiation Serve as highways for cell migration - selective barrier.
Molecular filter in the kidney glomerulus
