Fibrous proteins (biochem)

structure and function of fibrous proteins ( biochemistry)

1. Structure and Function of Fibrous Proteins Source: Biochemistry by Lippincott Maryam Fida (o-1827)

2. Collagen Most abundant protein in the human body (20-25% of body protein) A typical collagen molecule is a long, rigid structure in which three polypeptides (referred to as “α chains”) are wound around one another in a rope-like triple helix Triple stranded helix of collagen

3. Types of collagen More than twenty five collagen types Three polypeptide α chains are held together by hydrogen bonds between the chains α chains differ in amino acid sequence All approximately 1,000 amino acids long Most common collagen, type I, contains two chains called α1 and one chain called α2 (α1 2 α2), Type II collagen contains three α1 chains (α1 3 )

4. Structure of Collagen Amino acid sequence: - Gly –X–Y–, where X is frequently proline and Y is often hydroxyproline (but can be hydroxylysine ) Thus, most of the α chain can be regarded as a polytripeptide whose sequence can be represented as (– Gly –Pro– Hyp –) Hyp is hydroxyproline and Hyl is hydroxylysine

5. Triple-helical structure: Elongated, triple-helical structure that places many of its amino acid side chains on the surface Allows bond formation between the exposed R-groups of neighboring collagen monomers, resulting in their aggregation into long fibers

6. Hydroxyproline and Hydroxylysine : Result from the hydroxylation of some of the proline and lysine residues after their incorporation into polypeptide chains An example of posttranslational modification Hydroxyproline is important in stabilizing the triple-helical structure of collagen because it maximizes interchain hydrogen bond formation

7. These hydroxylation reactions require molecular oxygen, Fe 2+ and the reducing agent vitamin C (ascorbic acid) without which the hydroxylating enzymes, prolyl hydroxylase and lysyl hydroxylase , are unable to function. In the case of ascorbic acid deficiency (and, therefore, a lack of prolyl and lysyl hydroxylation), interchain H-bond formation is impaired, collagen fibers cannot be cross-linked, greatly decreasing the tensile strength of the assembled fiber. The resulting deficiency disease is known as Scurvy . Patients with ascorbic acid deficiency also often show bruises on the limbs as a result of subcutaneous extravasation of blood

8. Collagen diseases 1,000 mutations have been identified in 22 genes coding for twelve of the collagen types Defective Collagen Synthesis: Ehlers- Danlos syndrome (EDS) Osteogenesis imperfecta (OI)

9. Ehlers- Danlos syndrome (EDS) Can result from : Deficiency of collagen-processing enzymes e.g. lysyl hydroxylase deficiency or procollagen peptidase deficiency mutations in the amino acid sequences of collagen types I, III, or V most clinically important mutations are found in the gene for type III collagen (in blood vessels).

10. Osteogenesis imperfecta (OI) - Brittle bone syndrome Bones that easily bend and fracture Retarded wound healing and a rotated and twisted spine leading to a “humped-back” appearance are common features of the disease

11. Type I OI ( osteogenesis imperfecta tarda ): Decreased production of α1 and α2 chains Presents in early infancy with fractures secondary to minor trauma Prenatal ultrasound detects bowing or fractures of long bones

12. Type II OI is called osteogenesis imperfecta congenita : More severe. Patients die of pulmonary hypoplasia in utero or during the neonatal period Most patients with severe OI have mutations in the gene for either the pro-α1 or pro-α2 chains of type I collagen The most common mutations cause the replacement of glycine residues (in - Gly –X–Y–) by amino acids with bulky side chains. The resultant structurally abnormal pro-α chains prevent the formation of the required triple-helical conformation

13. Lethal form (type II) of osteogenesis imperfecta in which the fractures appear in utero, as revealed by this radiograph of a stillborn fetus.

14. Elastin Connective tissue protein with rubber-like properties Elastic fibers : Elastin and glycoprotein microfibrils Lungs, the walls of large arteries and elastic ligaments.

15. Structure of Elastin Insoluble protein polymer synthesized from a precursor, tropoelastin Tropoelastin : Linear polypeptide composed of about 700 amino acids that are primarily small and nonpolar (for example, glycine, alanine, and valine ) Also rich in proline and lysine Tropoelastin is secreted by the cell into the extracellular space . There it interacts with specific glycoprotein microfibrils , such as fibrillin , which function as a scaffold onto which tropoelastin is deposited

16. Mutations in the fibrillin-1 protein are responsible for Marfan syndrome Long Thin Extremities Dislocation of eye lens Aortic aneurysm Abnormal fibrillin protein is incorporated into microfibrils along with normal fibrillin , inhibiting the formation of functional microfibrils .

17. Disorders of Elastin Degradation α 1 - Antitrypsin (α 1 -AT, A1AT, currently also called α 1 -antiproteinase): Inhibits proteolytic enzymes (proteases or proteinases) that hydrolyze and destroy proteins α 1 -AT inhibits neutrophil elastase (protease released into the extracellular space, degrades elastin of alveolar walls and other structural proteins)

18. Role of α 1 -AT in the lungs The proteolytic activity of elastase can destroy the elastin in alveolar walls if unopposed by the inhibitory action of α 1 -AT Lung tissue cannot regenerate; emphysema results from the destruction of the connective tissue of alveolar walls In two to five percent of patients emphysema is inherited

19. Smokers A specific α 1 -AT methionine is required for the binding of the inhibitor to its target proteases. Smoking causes the oxidation and subsequent inactivation of that methionine residue, thereby rendering the inhibitor powerless to neutralize elastase

20. Smokers with α 1 -AT deficiency, therefore, have a considerably elevated rate of lung destruction and a poorer survival rate than nonsmokers with the deficiency The deficiency of elastase inhibitor can be reversed by weekly intravenous administration of α 1 -AT