Extracellular Matrix (Biochemistry) 2024 PDF

SBM 101: «Extracellular Matrix» Prof. Dr. Gül Güner Akdoğan November 4th, 2024  PLAN of TALK General Composition of Extracellular Matrix (ECM) Structure and Function of: 1. Fibrillar Proteins 2. Adhesive Glycoproteins 3. Proteoglycans At the end of this lecture, students sh...

SBM 101: «Extracellular Matrix» Prof. Dr. Gül Güner Akdoğan November 4th, 2024  PLAN of TALK General Composition of Extracellular Matrix (ECM) Structure and Function of: 1. Fibrillar Proteins 2. Adhesive Glycoproteins 3. Proteoglycans At the end of this lecture, students should be able to: Describe the composition of the ECM Define the terms: Fibrillar proteins, Proteoglycans, and Adhesive Glycoproteins Explain Collagen Structure, Function, and Types Explain Elastin Structure and Elasticity Compare and contrast elastin and collagen Cite the structure-functions of fibronectin and laminin (adhesive glycoproteins) Summarize the types of proteoglycans, structures, and function  Extracellular Matrix (EM): The milieu OUTSIDE the CELL  TERMINOLOGY ECM(EM) ( Extracellular Matrix):Hücre Dışı Matris Tensile strength: Gerilme direnci (resistance to elongation) Elasticity: Esneklik (Like a rubber band) Cell adhesion: Hücre yapışması (cells glue together) Mediate: Aracı olmak, koordine etmek(coordinate) Adhesive: Yapıştırıcı (act like a glue) Latent : Gizli (İnaktif) (hidden) Helix: Helezon (like a spiral) Regulate: Düzenlemek (control) Scaffold :Yapısal iskelet (skeleton)  EM FUNCTIONS SEM of a MYOBLAST Provides structural support secreting EM and elasticity Provides molecular scaffold for cell adhesion and migration Regulates cell differentiation and functional activitites of cells BASIC COMPONENTS OF ECM Fibrous proteins Collagen, Elastin Provide tensile strength and elasticity Proteoglycans: Protein-carbohydrate complexes. Give VOLUME… Support cell adhesion. Bind a several latent growth factors. Adhesive Proteins: Fibronectin, Laminin Mediate cell adhesion  FIBROUS PROTEINS Collagen - Elastin a-Helix or b- structure Generally polypeptide chains are parallel to the single axis Are mechanically strong and contain high proportion of cross-links  Collagen Molecules: Abundant Amino Acids: Glycine, proline, hydroxyproline Triple helix (three fibers interwined together) Synthesizdd as «procollagen- tropocollagen»  Fibril-forming or fibril-associated collagens are «insoluble». Degraded fragment of XVII, endostatin, inhibits angiogenesis and hence tumor growth  Crosslinking of Collagen Fibrils (Outside the Cell) Deaminated by the enzyme, «lysyl oxidase», to yield aldehyde groups, spontaneous covalent bonds between aldehyde groups (about every 67 nm) Names of cross-links: Lysinonorleucine, Pyridinium (PyD) and Deoxypyridinium- (dPyd) If crosslink is broken, collagen is easy to «tear»  Elastic Fibers Found throughout the body- Most prominent in skin, aorta,bronchioles Composed of fibrillin fibrils and elastin High synthesis rate in fetal and juvenile (young) fibroblasts Elastic fibers : ELASTIN Imparts (gives) elasticity to the tissue… Hydrophobic amino acids are abundant in its composition Insoluble protein.. Synthesized as “proelastin-tropoelastin” Cross-linked outside the cell forming insoluble “elastin” Elastin Polypeptide chains : Composed of alpha (α) and also beta β helix Forms cross-links with desmosine (Des) and isodesmosine (IsoDes) polyfunctional amino acids  ELASTIC FIBERS Elastic fibers permit long-range deformability and passive* recoil**. Elastic modulus is ~0.1 MPa. This function is crucial for arteries, lung, skin and other dynamic connective tissues that undergo cycles of extension and recoil. The major component of elastic fibers is the thread-like protein elastin Fibrillins provide an outer structure for amorphous, cross-linked elastin * Not requiring energy ** Take the original coiled (bobin) shape Elastin’s Insolubility and Cross-links Allow: Elasticity of arteries, lungs, and other dynamic connective tissues With aging, elastin is degraded and becomes inflexible  STOP AND THINK! Compare and Contrast Collagen and Elastin FIBROUS PROTEINS PROTEOGLYCANS ADHESIVE GLYCOPROTEINS Proteoglycans are proteins attached to GAGs GAG’s: Glycosaminoglycans Modification of the tetrasaccharide occurs in the ER  Proteoglycans / GAG’s Very diverse Different type of core protein (aggrecan, syndecan) Different composition of GAGs (chondroitin sulfate, heparin, heparan sulfate) Different lengths GAG’s are posttranslational modifications of a core protein Extracellular matrix proteoglycans  Hyaluronan is a polysaccharide 25,000 subunits Made directly outside the cell Most common No SO3 Joint fluid, wound healing, development Source of cell migration Degraded by hyaluronidase  Hyaluronates: Chondroitin sulfates: Dermatan sulfate: composed of D-glucuronate + GlcNAc composed of D-glucuronate composed of D-glucuronic acid + GalNAc-6 (or 4)-sulfate (GlcA) or L-iduronate (IdoA) + GalNAc-sulfate Hetereogenity in dermatan sulfate results from varying degrees of O-sulfatation and from the presene of the two No need to memorize!!! uronic acids. Keratan sulfates: Heparin and Heparan sulfates: composed of galactose + galactose- composed of D-glucuronate-2-sulfate + N-sulfo-D- 6-sulfate + GlcNAc-6-sulfate glucosamine-6-sulfate (heparans have less sulfate than heparins) Structure of Cartilage Proteoglycan Aggregate  STOP AND THINK! Summarize «proteoglycans’ properties» FIBROUS PROTEINS PROTEOGLYCANS ADHESIVE GLYCOPROTEINS  ADHESIVE GLYCOPROTEINS Long flexible molecules with domains for binding Bind ECM to the cells Bind to: collagen, proteoglycans, trans-membrane receptors, cell surface molecules, signaling molecules Selected Examples: Fibronectin, Laminin FIBRONECTIN: a dimer  Structure of Laminin (a large heterotrimeric multiadhesive matrix protein found in all basal laminae)  LAMININ Co-localisation with Type IV Collagen, Nidogen, and Perlecan Binds to basal membrane receptors Provides binding sites for Type IV collagen, heparan/heparane sulfate Model of the «Basal Lamina»  CONCLUSIONS ECM, is an outstanding example of “structure- function relationship” in biology ECM is NOT an inert file or packing material-it is a vital, dynamic,regulatory terrain of the body  SUMMARY OF KEY CONCEPTS Extracellular matrix (EM) structure-function relationshps Collagen (Col) Elastin Proteoglycans Glycoproteins (Ex: Fibronectin, Laminin) Basal Lamina- Basement membrane  REFERENCES PISCINGER,A. The Extracellular Matrix and Ground Regulation. North Atlantic Books, Berkeley, California,2004 AHMED N, DAWSON M, SMITH C & WOOD, E. Biology of Disease.Taylor & Francis, New York & Oxford, 2007. NAGASE, H, VISSE R & MURPHY G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovascular Research 2006; 69: 562- 573. STAMENKOVIC I. Extracellular matrix remodelling: the role of matrix metalloproteinases. Journal of Pathology 2003;200:448-464. CHIRCO R, LIU XW, JUNG K-K & CHOI KIM HR. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 2006; 25:99-113. JIANG Y, GOLDBERG ID & SHI YE. Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 2002; 21: 2245-2252. ROYCE PM, STEINMANN B (Eds). Connective Tissue and its Heritable Disorders:Molecular, Genetic, and Medical Aspects. Wiley-Liss,New-York, 1993. STREULI CH, GRANT ME (Ed). Extracellular Matrix Protocols, Humana Press,Totowa, New Jersey, 2000 Thank-you……