Cell-Extracellular Matrix Interactions

Transcription

1 Cell-Extracellular Matrix Interactions Extracellular Matrix (ECM) Organised network outside of the cell s plasma membrane Between cells Composition varies throughout the ECM Continuous sheet of ECM = Basement Membrane/Basal Lamina (BM) nm thick Surrounds epithelial and endothelial cells of many cell types Components = 2 network forming molecules = connected by entactin molecules Collagen IV Laminin Glycocalyx (GC) Layer close to the plasma membrane Made of carbohydrate projections from: Proteins Lipids Cell-Cell Interactions are mediated from the GC ECM Functions: 1. Mechanical Support Cell Matrix adhesion stabilises the position of the cell in a tissue Correct reposition of cells by migration in development and repair 2. Structural Strong to hold tendons Elastic allows movement 3. Extracellular communication medium GC talk from cell to cell 4. Regulates cell function Cell type can undergo its process Components: Collagen Laminins Proteoglycans Fibronectins

2 Collagen Fibrous glycoproteins found only in the ECM but most abundant fibroblast produces them 27 types Types restricted to particular bodily locations STRONG = high tensile strength Made of : Proline Hydroxy-Proline Hydroxylated Amino Acids = Hydrogen Bonds Hydroxy-Lysine Common Property TRIMER of polypeptide helical alpha chains that form a triple helix 1 types = homotrimer 2/3 types = heterotrimer Structure and Stability of Collagen I Hydrogen Bonding Within the collagen molecule triple helix Due to hydroxylated amino acids Covalent Bonding Between each of the triple helix structures Collagen molecules stack on top of one another creating a fibril Lysine and Hydroxy-Lysine Fibrils come together to form a collagen fibre Collagen Fibril Organisation Triple helix staggered rows can position themselves in a multitude of ways in the ECM Positioning = mechanical properties of an organ TENDONS - Parallel alignment of long axis of tendon - Increase strength CORNEAL STROMA - Meet at right angles - Strong but transparent Note: not all collagen form fibrils (collagen IV) but rather the collagen is part of the basal lamina netowrk Excess Collagen Production Accumulates at site of injury = SCAR Excess production in a location causes mechanical impairments = SKIN FIBROSIS, CYSTIC FIBROSIS Fibril fragile bones dwarfism Non-fibrillar kidney disease Deficient Collagen Production

3 Laminins Extracellular glycoproteins made of 3 polypeptide chains and linked by disulfide bonds Domains either end to interact with other proteins > 15 types Functions: Basal Lamina component Cell migration during development Embryogenesis Proteoglycans Protein-polysaccharide complex Core protein attached to carbohydrate (glycosaminoglycans/gags) Found in basal lamina Carbohydrate repeating disaccharide structure ve charge = attract water = hydrated gel Fibronectins 2 similar polypeptide chains joined by disulphide bonds near C-terminus Polypeptide 30 folded molecules 5/6 functioning domains Binding sites available for: other ECM components = collagen/proteoglycans receptors from other cell surfaces =integrins contain RGD sites Functions: Embryonic development by cell migration

4 Integrins Family of membrane proteins made of α (18 types) and β (8 types) subunits Binding of proteins < > integrins through tripeptide RGD Mediate cell-ecm interactions Connect intracellular and extracellular environments Inside out and outside in signalling Adhesion of cells to substratum of another cell Activation - Bent = inactive - Upright = active - Divalent metal ions cause conformational changes of bent < > upright Signalling 1. Inside Out Cytoplasm α and β subunits are together Talin binds to the subunits separating them Integrin Conformational change in molecule Extracellular Change allows ligands to bind to the extracellular matrix 2. Outside In Regulates cellular function e.g. proliferation, differentiation and survival Binding of ligand causes a cascade of effects allowing a certain process/signal to be understood by the cell E.G. Platelet Aggregation Blood clots form when platelets join together via their integrins RGD sequence needed Drugs used to inhibit these interactions

5 Cells < > ECM = Focal Adhesions ECM components (collagen/fibronectins/laminins) bind to integrin on the cell = OUTSIDE > IN Itegrin responds with a conformational change in its cytoplasmic domain: 1. Adaptor molecule bind to domain recruiting cytoskeleton elements 2. Activates protein kinases to create a downstream signalling cascade Role in Cell Kinetics cell spreading Cells < > Basal Lamina = Hemidesmosomes Specialised structure at the site of attachment of cells to basal lamina Components: Cytoplasmic intermediate filaments Adaptor molecules (plectin) Transmembrane proteins (integrin/bp180) Anchoring filament (laminin-5) Human Diseases Autoimmune disease Genetic disease from the proteins