L22 Extracellular Matrix Proteins PDF

L22 Extracellular Matrix Proteins: Structure, Functions & Disorders Prof. Nelofar Khan www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives: 1. List the fibrous proteins in the body and mention their general functions. 2. Describe the structure-function relationships of collagen. 3. Describe th...

L22 Extracellular Matrix Proteins: Structure, Functions & Disorders Prof. Nelofar Khan www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives: 1. List the fibrous proteins in the body and mention their general functions. 2. Describe the structure-function relationships of collagen. 3. Describe the biosynthesis and post-translational modifications of collagens and their clinical significance. 4. List the different types of collagens, tissue distribution and their functions. 5. List the common types of collagen disorders. 6. Describe the biochemical defect in marfan syndrome. • Reading: Satyanarayana U and Chakrapani U. Biochemistry; Elsevier; 5th Edition; 2020. ISBN- 978-8131262535. Chapter 22, pages 487. • Video Ehler Denlos Syndrome: https://youtu.be/_r2tm5idW2Y • Video Marfan Syndrome: https://youtu.be/p4Ev9KEyw78 Cells in tissues are surrounded by a complex substance called the extracellular matrix (ECM). The ECM contains three major classes of biomolecules: 1. Structural proteins: Collagen, Elastin and Fibrillin-1 2. Specialized proteins: such as Fibronectin and Laminin 3. Proteoglycans (i) Collagen Structure of Collagen • Collagen is the major component of most connective tissues, constitutes approximately 25% of the protein of mammals. • Collagen has a unique secondary structure known as Triple helix; • Basic structural unit is called tropocollagen; • Each tropocollagen molecule is made up of three α chains, each having about 1000 amino acid residues; • Each chain forms an extended left handed helix; • Each α chain contains a repeated sequence of (Gly-x-Pro/Hyp)n. • One third of the amino acids are glycine; and large number of Proline and hydroxyproline; Cont…Structure of Collagen • Nonstandard amino acids hydroxyproline and hydroxylysine are formed by the vitamin C requiring enzymes hydroxylases. • The 3 chains join each other to produce a super-helical structure, a tropocollagen; • Tropocollagen molecules associate in Quarter Staggered Arrangement to form Collagen fibrils. • Lysyl oxidase is responsible for cross linking the collagen fibrils by bonding lysine and hydroxylysine. • Vitamin C deficiency causes impaired inter chain H-Bonds within the triple helix. Additionally, collagen fibrils cannot cross link greatly decreasing the tensile strength of the collagen fiber. Molecular Structure of Collagen Synthesis of Collagen Types of collagen • The collagen gene family comprises 45 genes encoding 28 homo‐ or heterotrimeric collagen types. Type I, II and III are Fibril forming • Type I (most common): In bone, scar tissue, tendons, ligaments • Type II: Hyaline cartilage • Type III: Blood vessels, skin, muscle Type IV and VIII are network forming • Type IV: Lens of eye; basal lamina beneath epithelium (esp. in skin, beneath epidermis); capillaries, including glomeruli • Type VIII: Cornea and vascular endothelium Collagenopathies Number of genetic diseases result from abnormalities in the synthesis of collagen a. ▪ ▪ ▪ ▪ Ehlers-Danlos syndrome comprises a group of inherited disorders principal clinical features are hyperextensibility of the skin abnormal tissue fragility, and increased joint mobility clinical picture is variable, reflecting underlying extensive genetic heterogeneity b. Osteogenesis Imperfecta (Blue Sclera) ▪ Extremely fragile bones ▪ Caused by a defect in the gene that produces type 1 collagen, an important building block of bone. ▪ The severity depends on the specific gene defect. c. Alport syndrome ▪ a number of genetic disorders (both X-linked and autosomal) affects the structure of Type IV collagen fibers ▪ the major collagen found in the basement membranes of the renal glomeruli ▪ patients may eventually develop end-stage renal disease d. Epidermolysis bullosa ▪ the skin breaks and blisters as a result of minor trauma ▪ mutations affecting the structure of Type VII collagen ▪ Function of type VII collagen is to form delicate fibrils that anchor the basal lamina to collagen fibrils in the dermis e. Scurvy ▪ Also affects the structure of collagen ▪ Due to a deficiency of ascorbic acid and is therefore acquired and not a genetic disease ▪ Its major signs are bleeding gums, subcutaneous hemorrhages, and poor wound healing ▪ These signs reflect impaired synthesis of collagen due to deficiencies of prolyl and lysyl hydroxylases, both of which require ascorbic acid as a cofactor. (ii) Elastin (Another structural protein) ▪ Protein responsible for properties of extensibility and elastic recoil in tissues. ▪ Is present in large amounts in lung, large arterial blood vessels, elastic ligaments, skin, ear and cartilage. ▪ Elastin is synthesized as tropoelastin monomer. Some of the prolines of tropoelastin are hydroxylated to hydroxyproline by prolyl hydroxylase. ▪ Elastin exhibits a variety of random coil conformations that permit the protein to stretch and subsequently recoil ▪ Deletions in the elastin gene (located at 7q11.23) have been found in Williams-Beuren syndrome, a developmental disorder affecting connective tissue and the central nervous system. ▪ A decrease of elastin is found in conditions such as pulmonary emphysema and aging of the skin. (iii) Fibrillin-1 (A structural protein) ▪ Is a large glycoprotein (about 350 kDa) ▪ It is secreted into the extracellular matrix by fibroblasts ▪ Becomes incorporated into the insoluble microfibrils, which provide a scaffold for deposition of elastin. ▪ Fibrillin-1 is found in the zonular fibers of the lens, in the periosteum, and associated with elastin fibers in the aorta. ▪ (Note: The periosteum is a membrane that covers the outer surface of all bones, except at the joints of long bones). MARFAN SYNDROME ▪ It is inherited as an autosomal dominant trait caused by mutations in the gene (on chromosome 15) for fibrillin-1. This results in abnormal fibrillin and/or lower amounts being deposited in the ECM. ▪ It affects: ▪ Eyes (eg, causing dislocation of the lens, known as ectopia lentis) ▪ Skeletal system (most patients are tall and exhibit long digits [arachnodactyly] and hyperextensibility of the joints) ▪ Cardiovascular system (eg, causing weakness of the aortic media, leading to dilation of the ascending aorta). Marfan Syndrome (iv) FIBRONECTIN ▪ Important glycoprotein of ECM involved in cell adhesion & migration. ▪ Fibronectin are organized into functional domains which have heparin, fibrin, collagen, and cell surfaces binding functions. (v) LAMININ • It is a major protein component of renal glomerular & other basal laminas. • Basal laminas are specialized areas of the ECM that surround epithelial and some other cells, for eg: muscle cells. • The thick basal lamina of the renal glomerulus plays an important role in glomerular filtration. Let us summarize: • Structure of Collagen • EDS • Scurvy • Osteogenesis Imperfecta • Marfan Syndrome Thank You 19