Please enable JavaScript.
Coggle requires JavaScript to display documents.
Extracellular Matrix Interactions (Collagen (Collagen Synthesis (Synthesis…
Extracellular Matrix Interactions
ECM is a complex network of material e.g proteins/ polysaccharides that are secreted locally by cells and remain closely associated with them to provide
structural
,
adhesive
,and
biochemical signalling
support
In mammels ECM is composed of around 300 proteins , known as the core matrisome and includes
Collagen
structural proteins, provide strength and flexibility
Proteoglycans
Protein-polysaccharide complexes, provide the matrix
Glycoprotiens
adhesive glycoproteins, fibronectins and lamins. Allow cells to attach to the matrix
Collagen
over 20 different extracellular proteins and the most abundant
Principle function - provide support to tissue
All collagens are organised into triple helical structures composed of THREE COLLAGEN PEPTIDES
Secreted from cells and assembled into larger fibrils and fibers in the extracellular space
The Collagen triple helix
Polypeptide chains have about 330 Gly-X-Y repeats
Secreted through ER/ golgi form
collagen fibrils
Fibrils form collagen fibers, several um in diameter
Collagen Synthesis
Synthesis of procollagen begins on ribosomes of Rough endoplasmic reticulum
Golgi apparatus adds sugars
glycosylation
Facilitate zipper like formation and stabilisation of triple helices and 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 cross linked
Fibronectins
Sticky protein, Homodimeric (made of two identical monomers) cancer cells do not produce fibronectin
Binds to collagen, GAGS
Recognised by cell surface receptors
Roles of Fibronectin
In embryonic cell migration, the pathways followed by migrating cells are rich in fibronectin, suggesting it may guide the cells
Opsonization, wound healing and maintenance of cell shape
Many kinds of cancer cells do not produce fibronectin
Basal Lamina
Thin layer on which epithelial cells rest, Also surrounds muscle cells, adipose cells and peripheral nerves
Hetrotrimal = made of 3 chains of a,b +y
Lamins
Found mainly in the basal lamina
Separates epithelial cells from connective tissue
Heterotrimer a, b and y chains ( coded by 5,4,3 different genes)
Have several sites for binding type IV collagen, heparin, heparin sulfate and entactin and receptors on cell surfaces
Proteoglycans
Integral components of the plasma membrane with their core polypeptides embedded in the membrane
Has a number of GAG chains attached along the length of the protein
Hylauronans = major component. Extremely long, negatively charged polysaccharide
Integrins
Are a large family of cell surface receptors that bind to fibronectins or laminins
Integrate the cytoskeleton with the ECM
Structure
Consist of two large transmembrane polypeptides a and b
Differ from one another in binding specificity and sub unit sizes
extracellular parts of the a and b subunits form the binding sites of the integrin: specificity is dependant on the a unit
In mammels the 18 a subunits and 8 b subunits combine to form 24 different heterodimeric receptors- which exhibits distinct ligand binding specificities and tissue distribution
Dimers
Signalling
Inside out integrin signalling
intracellular activator, binds to the b integrin tail, leading to conformational changes that result in increased affinity for extracellular ligands
outside in integrin signalling
Integrin also behaves like traditional signalling receptors in transmitting information into cells.
Hemidesmosomes
Promote adhesion of the epithelial cells to the underlying basement membrane in the skin
ECM and human diseases
Mutations can cause a wide range of connective tissue disorders
Two mechanisms
First, secretion of the mutated ECM components can be reduced by mutations affecting synthesis or by structural mutations causing cellular retention or degration
Second, secretion of mutant protein can disturb crucial ECM interactions, structure and stability
Collagen diseases
over production Pulmonary fibrosis
Osteogenesis imperfecta = brittle bone syndrome mutation
ECM and cancer progession
Tissue can enter tumorigenic events. one of the earlier events = activated fibroblasts or CAFS, which contributes to abnormal ECM buildup and deregulated expression of ECM remodelling enzymes