CT FIBROUS PROTEINS

Towards Unbounded Thinking

Connective Tissue Fibrous Proteins: Shape and Function

General Information

  • Presented by: NGU Biochemistry Team

  • School Year: 2025/2026

Aim of the Lecture

  • Objective: To explain the structure-properties-function relationship of fibrous proteins.

Learning Objectives

By the end of this lecture, the student should be able to:

  • Explain how the structure of α-keratin offers external protection to the body.

  • Explain how the protein structure of elastin is able to stretch and reform itself.

  • Explain the four main stages of collagen synthesis: procollagen, tropocollagen, assembly, and crosslinking.

  • Describe four examples of collagen disorders in disease, including:

    • Osteogenesis imperfecta

    • Ehlers-Danlos syndrome

    • Scurvy

    • Lathyrism

Human Tissue Classification

Human cells are classified into five main types of tissues:

  1. Epithelial tissue

  2. Connective tissue

  3. Muscular tissue

  4. Nervous tissue

  5. Blood

Connective Tissue (CT)

  • Definition: Connective tissue fills the spaces between organs and tissues and provides structural and metabolic support.

  • Components:

    • Cells: Various cell types present within the tissue.

    • Extracellular Matrix (ECM): Includes water, minerals, proteoglycans, and fibrous proteins secreted by the cells.

  • Significance: The composition of the ECM determines the properties and functions of connective tissue.

    • Example: Calcified matrix forms bone or teeth.

Properties of Fibrous Proteins

  1. Extended Protein Structure: Fibrous proteins have a long, extended structure.

  2. Solubility: Generally insoluble in water or lipid bilayers.

  3. Secondary Structure: Simplistic, often dominated by one type of secondary structure.

  4. Quaternary Structure: Held together by covalent bridges.

Functions of Fibrous Proteins

Fibrous proteins play crucial structural roles in the body, including:

  • α-Keratin: Provides external protection and toughness; found in hair, nails, and the outer skin.

  • Elastin: Present in connective tissues; associated with elasticity and stretchability, found in ligaments, lung walls, and the aorta.

  • Collagen: Imparts tensile strength; present in tendons and bones.

  • Myosin: Provides contractile properties in muscle tissue.

α-Keratin

  • Structure: Dimer formed from two α-keratin α-helices.

    • Found in hair, nails, and the outer layer of skin.

    • Synthesized by epidermal cells.

Protein Structure of α-Keratin

  • Secondary Structure: Primarily consists of α-helices.

  • Amino Acid Composition: Rich in hydrophobic amino acids, particularly cysteine residues that form disulfide bridges.

    • Increased disulfide bridges correlate with enhanced strength of α-keratin.

Supersecondary Structure of α-Keratin

  • α-Keratin consists of the association of long parallel α-helices, contributing to its toughness.

  • Dimer Formation: Two parallel α-helices supercoil around each other to form a dimer. Dimer configurations lead to the assembly of protofibrils.

  • The staggered formation of protofibrils results in a four-stranded rope-like structure, accounting for the toughness of α-keratin.

Elastin

Structure and Function

  • Type: Insoluble, rubber-like protein.

  • Primary Component: Major component of elastic fibers, synthesized by fibroblasts and chondrocytes.

  • Location: Found in elastic ligaments, lung walls, and blood vessel walls (especially large arteries like the aorta).

  • Properties: Capable of significant stretch and returning to original size. Appears fibrous when extended and globular when relaxed.

  • Clinical Significance: Errors in the synthesis and degradation of elastin are linked to cardiovascular disease and lung emphysema.

Structure of Tropoelastin

  • Building Unit: Tropoelastin is secreted by cells into the extracellular space.

  • Amino Acid Composition: Rich in lysine; some lysine residues are oxidatively-deaminated to form allysine. Large hydrophobic peptides present that allow elastin structure to deform without forming hydrogen bonds.

Formation of Elastin

  • Crosslinking: Elastin is formed through the crosslinking of tropoelastin via lysine residues, creating a rubbery consistency.

    • Types of crosslinks include:

    • Desmosine Link: Formed from four lysine residues linking four tropoelastin molecules.

    • Lysinonorleucine Link: Formed by connecting two tropoelastin molecules with two lysine residues.

Desmosine Cross-link

  • Structure: Formed of three allysine (modified lysine) and one lysine residue.

  • Interconnectivity: Contributes to the rubbery network of elastin, with desmosine resulting from oxidative processes involving lysine.

Collagen

Overview

  • Abundance: Collagen is the most abundant protein in the body, particularly in connective tissues where tensile strength is vital.

  • Examples: Found in tendons, inner skin, cartilage, bones, and the cornea.

  • Types: There are 16 different types of collagen, with type I and type II being the most common.

    • Type I: Composed of two α1 chains and one α2 chain.

    • Type II: Consists of three α1 chains.

Structure of Collagen

  • Building Unit: Tropocollagen is the foundational unit, described as a long and thin fibrous protein composed of three coiled peptides [α-chains]. Each chain has a left-handed helix; their twisting forms a right-handed superhelix (the tropocollagen molecule).

Amino Acid Composition

  • Repeating Sequence: Collagen's α-chain contains a repeating triplet sequence Gly-X-Y, where:

    • Gly: Glycine is present in every third position.

    • X: Typically proline, and Y: Often hydroxyproline.

    • The X position can sometimes be lysine, while the Y position can be hydroxylysine.

    • Hydroxylysine residues may have glucose and galactose molecules attached, classifying collagen as a glycoprotein.

Structural Properties

  • Tight Helix Formation: Each turn of the collagen helix consists of three amino acid residues, making it tighter than other proteins that typically contain 3.3 residues per turn.

  • Arrangement: The presence of glycine allows peptide chains to come close together, forming a rigid alignment that contributes to the structural integrity of collagen.

  • Hydroxyproline: This amino acid is critical for hydrogen bonding between chains, reinforcing the structure of collagen.

  • Covalent Cross-linking: Adjacent polypeptide chains form covalent links, which impart tensile properties without breaking under strain.

  • Fibril and Fiber Formation: Burglarization into fibrils and fibers with a staggered array leads to marked flexibility.

Collagen Synthesis: Four Stages

  1. Formation of Procollagen: Synthesized in cells, hydroxylation of specific proline and lysine residues occurs (vitamin C as a cofactor), leading to procollagen assembly through disulfide bridges.

    • Medical Implications: Osteogenesis imperfecta associated with faulty collagen gene leading to weaker structures.

  2. Cleavage to Tropocollagen: Procured by procollagen peptidase resulting in the formation of a triple helix structure in tropocollagen.

    • Medical Implications: Ehlers-Danlos syndrome arising from incomplete cleavage prevents necessary crosslinks.

  3. Assembly of Tropocollagen: Forms a staggered array (1/4 shift) leading to calcium phosphate deposition crucial for bone formation. The interaction of hydroxyproline with the hydroxyls facilitates this self-assembly.

    • Medical Implications: Scurvy implicating the absence of hydroxylation leads to impaired assembly.

  4. Crosslinking of Collagen Fiber: Stabilization is achieved through covalent links formed by lysine residues, with the lysyl oxidase enzyme tripling modified lysine structures into allysine for stronger crosslinks.

    • Medical Implications: Lathyrism emerges due to inhibited lysine oxidase activity, affecting structural integrity.

Collagen Structural Strength

  • Strength Metrics: Collagen fiber demonstrates remarkable tensile strength, outperforming reinforced concrete, with a strength capacity of approximately 9,000g in fiber bundles measuring less than 1mm in diameter.

Collagen Defects and Associated Diseases

  1. Osteogenesis Imperfecta:

    • Characterized by brittle bone syndrome from a mutant collagen gene (glycine residue mutated).

    • Results in structural anomalies and skeletal deformities.

  2. Ehlers-Danlos Syndrome:

    • Involves excess procollagen due to reduced procollagen peptidase levels; structural defects in connective tissue are observed.

    • Patients exhibit hypermobility and easily stretchable skin.

  3. Scurvy:

    • Deficiency in Vitamin C leads to failure in hydroxylating proline to hydroxyproline, resulting in poor collagen structure and stability.

    • Symptoms: Fragile blood vessels, skin lesions, delayed wound healing.

  4. Lathyrism:

    • A dietary disease causing impaired crosslinking due to components from sweet pea or copper deficiency.

    • Symptoms include joint dislocations and weakened bone structure.

Further Readings

  • Recommended Texts:

    • Harvey RA & Ferrier DR. Lippincott’s Illustrated Reviews, Biochemistry, 5th edition, 2011.

    • Berg, Tymoczko, Stryer, 7th edition, 2012.

    • Stryer 3rd edition 1988.

  • Additional Notes: Review indicated errors in keratin structure; refer to Trends in Biochemical Sciences, Oct 1993 for clarification.