Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Extracellular Matrix Readings and Objectives • Reading – Cooper: Chapter 14 • Topics • The Extracellular Matrix • Composition • Cell-Matrix Interactions • Cell-Cell Interactions 2 Extracellular Matrix Introduction • Cell walls: bacteria, fungi, algae, and higher plants • Animal cell in tissues embedded in an extracellular matrix of proteins and polysaccharides Function • Provides structural support to cells and tissues • Important role in regulating cell behavior – Cell to cell interaction, communication 3 General Structure of Extracellular Matrix • Animal cells embedded in an extracellular matrix • Basal laminae: thin layer on which epithelial cells rest. Also surrounds muscle cells, adipose cells, and peripheral nerves • most abundant in connective tissues • Connective tissue – – – – loose connective tissue Bone tendon cartilage 4 Composition of Extracellular Matrix • Fibrous proteins • Polysaccharides- gel like environment • Adhesion proteins- link components of the matrix to one another and to cells • Different matrices have different amounts of each component – Tendons, rich in fibrous proteins – Cartilage, high in polysaccharides – Bone, calcium phosphate crystal deposition 5 Matrix composition: Collagen • Collagen- major structural fibrous protein • Forms triple helices • Triple helix domains: repeats of the amino acid sequence Gly-X-Y • Glycine in every 3rd position • X=Pro, packs helices closely • Y= hydroxyproline, synthesized in ER • Pro, Hpro stabilizes by helping H-bonding 6 Matrix composition: Collagen • Type I collagen- the most abundant • polypeptide chains have about 330 Gly-X-Y repeats • Secreted through ER/golgi, form collagen fibrils • Triple helical molecules are associated in regular staggered arrays • Covalent cross-links: lysine and hydroxylysine side chains • strengthen the fibrils • Fibrils form collagen fibers, several µm in diameter 7 Types of Collagen • Some are not fibril forming • Fibril-associated collagens: bind to collagen fibrils, link to others or to other matrix components • Network-forming collagens: have non helical interruption, cross-link to network • Anchoring fibrils: link basal laminae to underlying connective tissues • Transmembrane collagens: proteins that participate in cellmatrix interactions Network-forming collagens 8 Matrix Polysaccharides • Extracellular matrix gels are polysaccharides called glycosaminoglycans (GAGs). • GAGs are repeating units of disaccharides: One sugar is either N-acetylglucosamine or N-acetylgalactosamine, the second is usually acidic (glucuronic acid or iduronic acid). 9 Matrix Polysaccharides • sulfate groups make GAGs negatively charged • bind positively charged ions and trap water molecules to form hydrated gel • GAGs are linked to proteins to form proteoglycans 10 Matrix Adhesion proteins: Fibronectin • Link matrix components – to each other – to cell surfaces • Fibronectin : main adhesion protein of connective tissues • A homodimeric protein (2500 aa/subunit), binds – collagen and GAGs – cells • Recognized by cell surface receptors • Attachment of cells to the extracellular matrix 11 Matrix Adhesion proteins: Laminins • Laminin: adehsion protein of basal laminae • Heterotrimeric: α, β, and γ-chains (5, 4, 3 genes, respectively) • have binding sites for – cell surface receptors, eg integrins – type IV collagen – Proteoglycans • Assemble to cross-linked network • Linking cells and matrix 12 Cell-Matrix Interactions • Integrins: major cell surface receptors, involved in attachment of cells to the extracellular matrix • Transmembrane proteins, heterodimer of α and β subunits (18α, 8β) • Bind to short aa in, – Collagen – Fibronectin – laminin • also anchor the cytoskeleton to the extracellular matrix 13 Cell-Matrix Junctions Two types of cell-matrix junction • Focal adhesions: bundles of actin filaments are anchored to β subunits of integrins via – – • • • • α-actinin Vinculin via talin Assembly of focal adhesions Focal complex: small group of integrins Recruite Talin, Vinculin, αactinin and Formin Formin initiates actin bundles 14 Focal adhesions are reversible • • • • • Integrins can reversibly bind matrix components change conformation between active and inactive states Inactive state: integrin heads turned close to cell surface Cell signaling extends heads to matrix Migrating cells: focal adhesions form at the leading edge 15 Cell-Matrix Junctions: Hemidesmosomes • • • • Hemidesmosomes anchor epithelial cells to the basal lamina α6β4 integrins bind to lamins long cytoplasmic tail of β subunit binds to intermediate filaments via Plectin and BP230 and BP180 (similar to transmembrane collagens) 16 Cell-Cell interactions • Interactions between cells are critical for development and function of multicellular organisms • Cell-cell interactions: – Transient: activation of immune cells; migration to injury site – Stable: role in the organization of tissues. • Cell-Cell junctions allow rapid communication between cells • During embryo development, cells from one tissue specifically adhere to cells of the same tissue rather than cells of a different tissue 17 Cell-Cell interactions • Cell-cell adhesion- mediated by four groups of cell adhesion molecules • Selectins, integrins, the immunoglobulin (Ig) superfamily, and cadherins • Many adhesions are divalent cation-dependent, requiring Ca2+, Mg2+ or Mn2+ 18 Selectins • Selectins- transient interactions between leukocytes and endothelial cells • Leukocytes slow down, flattened, migrate from the circulation to sites of tissue inflammation • initial adhesion • stable adhesions binding of integrins to intercellular adhesion molecules (ICAMs) on endothelial cells 19 Cell to Cell Junctions Four types of Cell-Cell connections in animal cells • Adherens Junctions • Desmosomes • Tight Junctions • Gap Junctions 20 Adherens Junctions • Cadherin form stable cell-cell connections involve actin filaments • Also include β-catenin, p120, and α-catenin, • β-catenin and p120 bind to cadherin and help maintain stability • β-catenin binds α-catenin that interacts with actin filament of cytoskeleton 21 Desmosomes • link the intermediate filament of adjacent cells • Desmoglein and desmocollin (transmembrane cadherins) bind by heterophilic interactions across the junction • Plakoglobin and plakophilin bind to the cadherins and link to the intermediate filament binding protein, desmoplakin 22 Tight Junctions • Tight junctions provide minimal adhesive strength between the cells, usually associated with adherens junctions and desmosomes in a junctional complex 23 Tight Junctions • Tight junctions in epithelial cell form a seal that prevents free passage of molecules and ions between cells • separate apical and basolateral domains of the plasma membrane • prevent free diffusion of lipids and membrane proteins 24 Tight Junctions • transmembrane proteins, occludin, claudin, and junctional adhesion molecule (JAM), anchored on F-actin • Bind similar proteins on the adjacent cell • Sealing the space between cells 25 Gap Junctions • open channels through the plasma membrane • allowing ions and small molecules to diffuse freely • Proteins and nucleic acids can not pass through • heart muscle cells, passage of ions through gap junctions synchronizes the contractions of neighboring cells • allow passage of some signaling molecules, such as cAMP and Ca2+, coordinating responses of cells in tissues 26 Gap Junctions • Gap junctions are made of transmembrane proteins in the connexin family • 6 connexins form a cylinder with an open aqueous pore in its center, called a connexon • Connexons in the plasma membrane adjacent cells align • form open channels between the two cytoplasms 27 Gap Junctions • Specialized gap junctions occur on specific nerve cells and form an electrical synapse • Individual connexons can be opened or closed • When open, they allow rapid passage of ions between the two nerve cells 28