Elastin

ELASTIN

In contrast to collagen, which forms fibers that are tough and have high tensile strength, elastin is a connective tissue protein with rubber-like properties. Elastic fibers composed of elastin and glycoprotein microfibrils are found in the lungs, the walls of large arteries, and elastic ligaments. They can be stretched to several times their normal length but recoil to their original shape when the stretching force is relaxed.

 A. Structure

Elastin is an insoluble protein polymer synthesized from a precursor, tropoelastin, which is a linear polypeptide composed of about 700 amino acids that are primarily small and nonpolar (for example, glycine, alanine, and valine). Elastin is also rich in proline and lysine but contains scant hydroxyproline and hydroxylysine. 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. Some of the lysyl side chains of the tropoelastin polypeptides are oxidatively deaminated by lysyl oxidase, forming allysine residues. Three of the allysyl side chains plus one unaltered lysyl side chain from the same or neighboring polypeptides form a desmosine cross-link (Figure 4.12). This produces elastin, an extensively interconnected, rubbery network that can stretch and bend in any direction when stressed, giving connective tissue elasticity (Figure 4.13). Mutations in the fibrillin-1 protein are responsible for Marfan syndrome, a connective tissue disorder characterized by impaired structural integrity in the skeleton, the eye, and the cardiovascular system. With this disease, abnormal fibrillin protein is incorporated into microfibrils along with normal fibrillin, inhibiting the formation of functional microfibrils. [Note: Patients with Marfan syndrome, OI, or EDS may have blue sclerae due to tissue thinning that allows underlying pigment to show through.]

Figure 4.12 Desmosine cross-link in elastin.

Figure 4.13 Elastin fibers in relaxed and stretched conformations.

B. Role of α1-antitrypsin in elastin degradation

1. α₁-Antitrypsin: Blood and other body fluids contain a protein, α1-antitrypsin (AAT or A1AT), which inhibits a number of proteolytic enzymes (called proteases or proteinases) that hydrolyze and destroy proteins. [Note: The inhibitor was originally named α1-antitrypsin because it inhibits the activity of trypsin, a proteolytic enzyme synthesized as trypsinogen by the pancreas.] AAT has the important physiologic role of inhibiting neutrophil elastase, a powerful protease that is released into the extracellular space and degrades elastin of alveolar walls as well as other structural proteins in a variety of tissues (Figure 4.14). Most of the AAT found in plasma is synthesized and secreted by the liver. AAT comprises more than 90% of the α1-globulin fraction of normal plasma. Extrahepatic synthesis occurs in monocytes and alveolar macrophages, and may be important in the prevention of local tissue injury by elastase.

Figure 4.14 Destruction of alveolar tissue by elastase released from neutrophils activated as part of the immune response to airborne pathogens.

2. Role of α₁-antitrypsin in the lungs: In the normal lung, the alveoli are chronically exposed to low levels of neutrophil elastase released from activated and degenerating neutrophils. The proteolytic activity of elastase can destroy the elastin in alveolar walls if unopposed by the action of AAT, the most important inhibitor of neutrophil elastase (see Figure 4.14). Because lung tissue cannot regenerate, the destruction of the connective tissue of alveolar walls results in emphysema.

3. Emphysema resulting from α₁-antitrypsin deficiency: In the United States, approximately 2%–5% of patients with emphysema are predisposed to the disease by inherited defects in AAT. A number of different mutations in the gene for AAT are known to cause a deficiency of the protein, but one single purine base mutation (GAG to AAG, resulting in the substitution of lysine for glutamic acid at position 342 of the protein) is clinically the most widespread. The mutation causes the normally monomeric AAT to polymerize within the endoplasmic reticulum of hepatocytes, resulting in decreased secretion of AAT by the liver. Consequently, blood levels of AAT are reduced, decreasing the amount that gets to the alveoli. The polymer that accumulates in the liver may result in cirrhosis (scarring of the liver). In the United States, the AAT mutation is most common in Caucasians of Northern European ancestry. An individual must inherit two abnormal AAT alleles to be at risk for the development of emphysema. In a heterozygote, with one normal and one defective gene, the levels of AAT are sufficient to protect the alveoli from damage. [Note: Methionine 358 in AAT is required for the binding of the inhibitor to its target proteases. Smoking causes the oxidation and subsequent inactivation of the methionine, thereby rendering the inhibitor powerless to neutralize elastase. Smokers with AAT 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 treated by weekly augmentation therapy, that is, intravenous administration of AAT. The AAT diffuses from the blood into the lung, where it reaches therapeutic levels in the fluid surrounding the lung epithelial cells.