Extracellular matrix
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EXTRACELLULAR MATRIX AND CELL INTERACTIONS
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Extracellular matrix
- 1. Extracellular matrix Extracellular matrix z Network of proteins and carbohydrates that binds cells together z Supports and surrounds cells z Regulates cells activities z Lattice for cell movement Extracellular matrix molecules z Only 5 classes of macromolecules z Collagens z Elastic fibers z Proteoglycans z Hyaluronan z Adhesive glycoproteins Insoluble – can not be hydrated Soluble – easily hydrated z They can be mixed up in different proportions for different functions Functions z Mechanical support z Embryonic development z Pathways for cellular migration z Wound healing z Management of growth factors Collagen z Major insoluble fibrous protein of the extracellular matrix and connective tissue z Most abundant protein in animals z Made by fibroblasts and some epithelial cells Collagen – molecular structure z Triple helix of polypeptides z Each polypeptide is a left-handed helix too
- 2. Types of collagen z Fibrillar z Forms structures such as tendon or cartilage z Sheet forming z Connecting z Supports and organizes fibrous collagen z Transmembrane Fibrillar collagen I z Basic unit – triple helix 300 nm long z 2 α1 and 1 α2 molecules z Collagen fibrils form by lateral interactions of triple helices z Stabilized by covalent bonds z Displacement by 67 nm (gives the striated look) The basic structural unit of collagen Assembly of collagen fibers z Synthesized in secretory pathway as procollagen z Glycosylation in ER and Golgi z Helix formation in ER z Disulfide bonds that are cleaved later z Assembly outside ! Sheet forming collagen z Polymerizes into sheets z Forms basal membranes – collagen IV z Collagen VIII – Descemet’s membrane of cornea Collagen IV z A helix interrupted about 24 times by segments that can not form a helix z Globular domains at both C- and N-termini
- 3. Collagen IV z Nonhelical domains introduce flexibility z C-terminus globular domains associate with each other z Helical domains associate laterally to form branching strands Connecting collagens z Link fibrillar and sheet forming collagens to into networks and connect them to other structures z Collagen VI – short helices interspersed with globular domains z Align collagen I into parallel structures Connecting collagens z Collagen IX has two rigid helices connected by the flexible kink z The globular N-terminus binds to proteoglycans in the extracellular matrix z Links collagen II to glycosoaminoglycans (provides cushion for compression as in cartilage) Elastic fibers z Found throughout the body z Most prominent in skin z Composite of fibrillin fibrils and elastin z Synthesized only by fetal and juvenile fibroblasts z Whatever is made by puberty has to last until the end z Loss is responsible for wrinkles Fibrillin z Tread like protein z Forms 10 nm microfibrils z Found in elastic fibers and basal lamina z Linear molecule with independently folded domains Elastin z A polymer of tropoelastins z Tropoelastins form a family of closely related proteins z Products of a single gene and alternative splicing
- 4. Elastin z Continuous random network of elastin polypeptides z Helical domains separate random chains rich in hydrophobic residues Soluble components of extracellular matrix z Proteoglycans z Form highly hydrated gel responsible for volume of extracellular matrix z Hyaluronan z Hydrated polysaccharide z Makes matrix resilient to compression z Multiadhesive matrix proteins z Long flexible molecules that bind other matrix components and cells Proteoglycans z Diverse group of proteins with multiple polysaccharide chains z Found in connective tissues and extracellular matrix z Also attached to the surface of many cells z Responsible for volume of extracellular matrix z Highly hydrated Proteoglycans z Consist of multiple glycosaminoglycans (GAGs) posttranslationally added to a core protein Proteoglycans z Very diverse z Different type of core protein (aggrecan, syndecan) z Different composition of GAGs (chondroitin sulfate, heparin, heparan sulfate) z Different lengths GAG synthesis z GAGs are posttranslational modifications of a core protein z Core protein is synthesized in secretory pathway z Polysaccharides are added in ER by glycosyl transferases z Elongated and modified in Golgi
- 5. Functions of proteogylcans z Structural – elastic space fillers z Limit diffusion of macromolecules z Impede passage of microorganisms z Act as lubricants in the joints z Regulate cell motility and adhesion Other (nonstructural) functions of proteoglycans z Sequestration of growth factors z Present hormones to cell-surface receptors Proteoglycans z Assemble into aggregates with hyaluronan as a core of the aggregate Hyaluronan a.k.a. hyaluronic acid, hyaluronate z Major component of proteoglycans z Extremely long, negatively charged polysaccharide z Resists compression z Swollen gel creates turgor pressure z Forms viscous, hydrated gels z Large number of anionic residues on the surface bind water Hyaluronan z Hyaluronan keeps cells apart from one another z Facilitates cell migration z Surrounds migrating and proliferating cells z Inhibits cell-cell adhesion Adhesive glycoproteins z Long flexible molecules with domains for binding z Collagen z Other matrix proteins z Polysaccharides z Cell surface molecules z Signaling molecules
- 6. Adhesive glycoproteins z Attach cells to the extracellular matrix z Regulate cell attachment z Migration z Cell shape z Organize components of the matrix z Most bind to integrins – cellular adhesion receptors Laminins z Adhesive glycoproteins present in basal lamina z Basal lamina guides cells during development z Cells migrate along laminin containing surfaces z Cross-shaped proteins z As long as basal lamina is thick z 3 subunits z High affinity binding sites for z Heparan sulfate z Collagen IV z Cellular adhesion receptors Basal lamina z A thin planar assembly of extracellular matrix proteins z Basis is formed by collagen IV and laminin Interaction of the basal lamina with adjacent cells z Collagen IV and laminin interact with cell surface integrins and bind adjacent cells to basal lamina z Basal lamina guides cells during development z Cells migrate along laminin containing surfaces Basal lamina is structured differently in different tissues z Polarized cells z Filter that regulates passage of nutrients z Smooth muscle z Maintenance of integrity Basal lamina is structured differently in different tissues z Kidney glomerulus z Separates two cell layers z Double thickness lamina – both layers produce the basal lamina z Filters blood to form urine
- 7. Fibronectins z Attach cells to matrices that contain fibrous collagen z Essential for migration and cellular differentiation Tenascin z Expressed in embryonic tissues, wounds and tumors z Plays a role in development z Modular protein with 6 arms z Binds to cells via integrins