Fibrous Proteins: Collagen and Elastin

Comprehensive practice flashcards on fibrous proteins, covering the structure, tissue distribution, biosynthesis, and associated pathologies of collagen and elastin, including Scurvy, Osteogenesis imperfecta, Ehlers-Danlos syndrome, Marfan syndrome, and alpha-1-antitrypsin deficiency.

What are the four primary fibrous proteins highlighted in the lecture?

Collagen, elastin, keratin, and fibroin.

How do fibrous proteins differ from globular proteins regarding structure and water solubility?

Fibrous proteins have an extended, simple secondary structure based on one type only (high $\alpha$-helix or $\beta$-sheet content) and are insoluble in water or lipid bilayers. Globular proteins have a compact structure, a complex secondary structure mixing $\alpha$-helices, $\beta$-sheets, and loops, and are soluble in water or lipid bilayers.

How do the biological functions of globular proteins differ from those of fibrous proteins?

Globular proteins function across all aspects of metabolism (such as enzymes, transport, cell protection, and hormones), whereas fibrous proteins provide structural support to the body (in tendons, bones, muscle, ligaments, hair, and skin).

What is the quaternary structure of a typical collagen molecule?

A long, rigid structure composed of three polypeptide chains (termed "$\alpha$ chains") wound around one another in a rope-like triple helix.

How does the structural arrangement of collagen fibers correlate with their specific functions in tendons, bone, and the cornea?

In tendons, collagen is bundled in tight, parallel fibers to provide great tensile strength. In bone, fibers are arranged at angles to resist mechanical shear from any direction. In the cornea, collagen is stacked to transmit light with minimal scattering.

What creates the characteristic striated banding pattern observed in negatively stained collagen fibrils under an electron microscope?

The staggered arrangement of individual collagen molecules, which produces alternating gap regions with heavy staining and non-gap regions with light staining.

What is the chain composition and typical tissue distribution of Type I collagen?

Type I collagen is composed of two $\alpha_1$ chains and one $\alpha_2$ chain ($\alpha 1_2 \alpha 2$). It is found in elements of high tensile strength, including skin, bone (synthesized by osteoblasts), tendons, dentin, fascia, cornea, blood vessels, and late wound repair.

What is the chain composition and typical tissue distribution of Type II collagen?

Type II collagen is a homotrimer consisting of three $\alpha_1$ chains ($\alpha 1_3$). It is restricted to cartilaginous structures, including hyaline cartilage, intervertebral disks, the nucleus pulposus, and the vitreous body of the eye.

Where is Type III collagen primarily found, and what is its distinctive tissue characteristic?

Type III collagen is found in distensible tissues such as blood vessels, skin, uterus, fetal tissue/skin, and in early wound repair (reticulin).

Which collagen types are classified as network-forming, and what architectural structures do they form?

Types IV and VII. Type IV forms a two-dimensional meshwork in basement membranes (basal lamina) and the lens, while Type VII is found beneath stratified squamous epithelia.

What is the function of fibril-associated collagens such as Types IX and XII?

They bind to the surface of collagen fibrils, linking fibrils to one another and to other components within the extracellular matrix.

What characteristic amino acid sequence repeat is found along collagen $\alpha$ chains?

The repeating tripeptide motif $-\text{Gly}-X-Y-$, where $X$ is frequently proline, $Y$ is often hydroxyproline (or hydroxylysine), and glycine occurs at every third position.

Why is the presence of glycine at every third position critical to collagen triple helix stability?

Glycine has the smallest amino acid side chain (a single hydrogen atom), allowing the three polypeptide $\alpha$ chains to pack closely together within the tight interior of the triple helix.

What is the structural role of hydroxyproline in collagen?

Hydroxyproline maximizes interchain hydrogen bond formation between the $\alpha$ chains, providing thermal and mechanical stability to the triple-helical structure.

What enzymes catalyze the hydroxylation of proline and lysine residues, and what cofactors and cosubstrates are required?

Prolyl hydroxylase and lysyl hydroxylase. They require molecular oxygen ($\text{O}_2$), $\alpha$-ketoglutarate, ascorbate (vitamin C), and ferrous iron ($\text{Fe}^{2+}$).

What intracellular steps occur in the synthesis of procollagen prior to its secretion into the extracellular matrix?

1. Translation of preprocollagen chains on the rough endoplasmic reticulum (RER) and cleavage of the signal peptide.\n2. Hydroxylation of specific proline and lysine residues.\n3. Glycosylation of selected hydroxylysine residues with glucose and galactose.\n4. Formation of interchain disulfide bonds at the C-terminal propeptide extension.\n5. Triple-helix folding to yield procollagen, which is packaged into Golgi secretory vacuoles.

What extracellular modification converts soluble procollagen into insoluble tropocollagen?

Cleavage of the N-terminal and C-terminal propeptides by extracellular procollagen peptidases.

What enzyme mediates the cross-linking of collagen fibrils outside the cell, and what reaction does it catalyze?

Lysyl oxidase, a copper-dependent ($\text{Cu}^{2+}$) extracellular enzyme, oxidatively deaminates some lysyl and hydroxylysyl residues into reactive aldehyde derivatives (allysine and hydroxyallysine), which undergo condensation reactions to form covalent cross-links.

What is the biochemical cause and clinical presentation of Scurvy?

Vitamin C (ascorbate) deficiency impairs prolyl and lysyl hydroxylase activity, producing unstable collagen triple helices. Symptoms include irritability, fatigue, joint pain, rough scaly skin, petechiae, corkscrew hair, loose teeth, swollen bleeding purple gums, and dehiscence of previously healed wounds.

What genetic defect is responsible for Osteogenesis imperfecta, and what is its molecular consequence?

Mutations in the gene encoding Type I collagen, which produce structurally abnormal chains that prevent proper folding into a triple helix.

What collagen defects characterize Ehlers-Danlos syndrome?

Clinically important mutations in the gene for Type III collagen lead to potentially lethal vascular problems; defects in Type I collagen fibrils result in hyperelastic/stretchy skin and loose, hypermobile joints.

How is normal collagen degraded during growth and tissue remodeling?

Collagen molecules have half-lives of several years and are degraded by collagenase, which cleaves the intact triple-helical molecule into fragments that are subsequently denatured and hydrolyzed by peptidases.

In which anatomical locations is elastin predominantly found, and what mechanical property does it provide?

Elastin is found in the lungs (and alveoli), walls of large elastic arteries (such as the thoracic aorta), and elastic ligaments (such as ligamenta flava). It confers rubber-like elasticity, enabling tissues to stretch several times their length and recoil passively.

How does the amino acid composition of elastin differ from that of collagen?

Elastin is rich in proline and lysine but contains very little hydroxyproline and virtually no hydroxylysine, and it lacks the repeating $\text{Gly}-X-Y$ triple-helix motif.

What are the roles of Elastin-Binding Protein (EBP) and Fibulin-4 during elastin biosynthesis?

EBP acts as a molecular chaperone in the RER that binds tropoelastin (TE) and guides it through the Golgi to the cell membrane. Fibulin-4 aligns secreted TE molecules and mediates their interaction with lysyl oxidase for cross-linking.

Identify the cross-linking structure shown in this chemical diagram:

Desmosine cross-link, formed from four lysine residues (three oxidatively deaminated to allysine and one unmodified lysine) catalyzed by lysyl oxidase.

What is the genetic etiology and inheritance pattern of Marfan syndrome?

An autosomal dominant mutation in the fibrillin-1 gene ($FBN1$) located on chromosome $15$.

What cardiovascular complication is identified by the arrow in this sagittal contrast CT scan of a patient with Marfan syndrome?

Aortic root dilation, which predisposes patients to aortic aneurysms and aortic dissection.

What two chest wall deformities common in Marfan syndrome are depicted in these illustrations?

Pectus excavatum (indented breastbone, left) and pectus carinatum (protruding breastbone, right).

What major ocular and skeletal manifestations are characteristic of Marfan syndrome?

Ocular: ectopia lentis (lens dislocation) and severe myopia. Skeletal: tall stature, long extremities, arachnodactyly, joint hypermobility, high-arched palate, scoliosis/hyperkyphosis, and pes planus.

What is the pathophysiological mechanism of lung damage in $\alpha_1$-antitrypsin deficiency?

Neutrophil elastase released in the alveoli by activated and degenerating neutrophils is normally inhibited by $\alpha_1$-antitrypsin ($\alpha_1\text{-AT}$). In $\alpha_1\text{-AT}$ deficiency, unopposed elastase activity destroys alveolar elastin walls, resulting in emphysema (with an increased risk in smokers) and cirrhosis.

How can the deficiency of elastase inhibitor in $\alpha_1$-antitrypsin deficiency be treated medically?

By weekly intravenous administration of purified $\alpha_1$-antitrypsin ($\alpha_1\text{-AT}$).