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Extracellular Matrix Interactions (Outside the cell - facing away, Cells…
Extracellular Matrix Interactions
Outside the cell - facing away
Cells respond to molecular ques
ECM is complete network of material such as proteins and polysaccharides
Secreted locally by cells
Remain closely associated with them to provide structural adhesive and biochemical signalling support
In mammals ECM 300 proteins
Called core matrisome
Includes proteins - collagen, proteoglycans, glycoproteins.
10% of human genome deals with extracellular organisation
Macromolecules of ECM
Structural proteins - collagen and elastin provide strength and flexibility
Protein-polysaccharide complexes, proteoglycan that provide the matix
Adhesive glycoproteins, fibronectin and lamins - allow cells to attach to the matrix
Mammalian Matrisome
300 proteins to the core martisome
43 are collagen subunits
36 proteoglycans
200 complex glycoproteins
Parts of the ECM
Collagen
Fibronectin
Laminin
Proteoglycan
Intergrin
Collagen
Over 20 different ECM proteins
Most abundant proteins in the animal kingdom
Principal function to provide structural support to tissues
Organised into triple helical structure composed of three collagen peptides
Secreted from cells and assembled into larger fibrils and fibres in the EC space
Collagen triple helix
Polypeptide chains have 330 Gly-X-Y repeats
Secreted through ER/Golgi from collagen fibrils
Fibrils form collagen fibers - several um in diameter
Collagen Synthesis
Being on ribosomes in RER
From trimers and glycosylated
Zipper like formation and stabilisation of triple helices
Binding by chaperone Hsp47
Procollagen transported to golgi complex folded and secreted as precollagens
N and C terminal pro-peptides removed and trimers assemble into fibrils and are covalently crossed linked
Fibronectins
Sticky protein, homodimer protein
Made of 2 identical monomers
Main adhesion protein of connective tissues
2500 amino acids/subunits
Bind to collagen GAG
Recognised by cell surface receptors
Roles of Fibronectin
In embryonic cell migration the pathways followed by migrating cells are rich in fibronectin - it may guide the cells
Opsonisation, wound healing and maintenance of cell shape.
Many types of cancer cells do not produce fibronectin
Basal Lamina
Thin layer which epithelial cells rest
Surround muscle cells, adipose cells and peripheral nerves
Laminins
Founds mainly in the basal lamina
Separates epithelial cells from connective tissues
Heterotrimer a, B and y-chains (coded by 5,4,3 different genes)
They have several sites for binding
Type IV collagen
Heparin
Heparin sulfate
Entactin
Receptors on cell surface
Proteoglycans
Integral components of plasma membrane
Core plypeptides embedded in the membrane
Each proteoglycan has a number of GAG chains attached along the length of the protein
Integrins
Large family of cell surface receptors
Bind to fibronectins or laminins
Intergrate the cytoskeleton with the ECM
Important in cell division
Structure of Integrins
2 large transmembrane polypeptides a & B
Differ from one another in binding specificity and subunits sizes
Extracellular parts of the a & B subunits from the binding sites of the intergrin
The specificity is mainly dependent on the a unit
In mammal the 18 a-subunits and 8 B-subunits combine to form 24 different heterodimeric receptors
Each exhibits distinct ligand binding specificities and tissue distribution
Integrin Signalling
During inside-out integrin signalling and intracellular activator, such as talin binds to B-integrin tail
Leads to conformational changes
Results in increased affinity for extracellular ligands.
Integrins also behave like traditional signalling receptors in transmitting information into cells by outside-in signalling.
The combination of these two events leads to intracellular signals that control cell polarity, cytoskeletal structure, gene expression and cell survival and proliferation
Hyaluronans
Major component of proteoglycans
Extremely long
Negatively charged polysaccharide
Form viscous, hydrated gels
Large number of anionic residues on the surface bind water
Hemidesmosomes
Promote the adhesion of epithelial cells to the underlying basement membrane in skin
Protein-protein interaction shows alpha6beta4 integrin transduce signals from the extracellular matrix to the interior of the cell
Modulate the organisation of the cytoskeleton, proliferation, apoptosis and differentiation
ECM and human diseases
Tissue specific ECM are crucial for normal development and tissue function
Mutations in ECM genes result in range of serious inherited connective tissue disorders
Mutations cause ECM dysfunction by combinations of 2 mechanisms
1st secretion of mutated ECM components can be reduced by mutation affecting synthesis or by structural mutation causing cellular retention and/or degradation
2nd secretion of mutant protein can disturb crucial ECM interaction, structure and stability
Collagen Diseases
Lung-pulmonary fibrosis = Overproduction of collagen liver
Atheroclerosis = over consumption of alcohol
-Ehlers-Danios Syndrome = decreased levels in synthesis of type 1 or 3 collagen
Osteogenesis Imperfecta brittle bone syndrome = mutation in type 1 procollagen fail to assemble triple helix degrade imperfect collagen