Fibrous Proteins

Collagen Fiber Formation and Structure

• Collagen fibers are formed from precursor alpha chains inside the endoplasmic reticulum (RER), progressing to procollagen, collagen molecules outside the cell, collagen fibrils, and finally collagen fibers.
• The formation of collagen fibrils involves the assembly of individual triple helical collagen molecules into micron-length fibrils with a regular axial periodic "D-banding" pattern.
• Collagen has a highly stable half-life, ranging from several days to several years, and any mutation affecting its ability to form cross-linked fibrils impacts its stability.
• Collagen degradation is catalyzed by collagenases during tissue remodeling or in response to tissue growth or injury, resulting in the breakdown of collagen into smaller fragments and individual amino acids.
• Collagen plays a crucial role in maintaining homeostasis by providing structural support to tissues, contributing to wound healing, blood clotting, and vascular health.
• Collagen interacts with platelets and the coagulation cascade to initiate blood clot formation, contributing to the prevention of excessive bleeding and the maintenance of blood vessel integrity.
• Collagenopathies, such as Ehlers Danlos Syndrome, are a heterogeneous group of connective tissue disorders characterized by stretchy skin, loose joints, and other symptoms, with various genetic causes and incidence rates.
• Missense mutations in collagen can have a more severe impact than nonsense alleles, as they can act as dominant negative events, hindering proper helix formation and resulting in non-functional trimers.
• Osteogenesis imperfecta, also known as brittle bone disease, is a heterogeneous group of familial disorders resulting from the loss of the triple helix, leading to fragile bones.
• Classical Ehlers Danlos Syndrome affects Type V collagen, while other types are caused by pathological variants in Type III collagen or lysyl hydroxylase.
• The most common type of Ehlers Danlos Syndrome is the hypermobile type, occurring with an incidence of about one in 3-5,000, and the cause is unknown.
• Collagen plays a critical role in various physiological processes, including wound healing, blood clotting, and maintaining the integrity of connective tissues, contributing to overall homeostasis.

Connective Tissue Disorders and Proteins: Osteogenesis Imperfecta, Scurvy, Elastin, and More

• Osteogenesis imperfecta presents in various types, with different severities and outcomes, caused by mutations affecting collagen production and structure.
• Vitamin C deficiency leads to scurvy, characterized by bruising, loose teeth, and fragile capillaries due to the absence of crosslinking from ascorbate.
• Elastin is a connective tissue protein with rubber-like properties, providing tissues with the ability to stretch and recoil, found in lungs, blood vessels, and skin.
• Collagen and elastin are different in genetic types, structure, and synthesis, with collagen having a triple helix structure and elastin forming a random coil conformation allowing stretching.
• Elastin is synthesized as a soluble linear polypeptide monomer, tropoelastin, rich in proline and lysine, and interacts with glycoprotein microfibrils outside the cell.
• Elastin fibers are composed of fibrillin and elastin, with fibrillin being a glycoprotein found in microfibrils, and mutations in fibrillin-1 gene cause Marfan syndrome.
• Desmosine is a tetrafunctional cross-link unique to elastin, forming an extensive interconnected network, providing elasticity to connective tissue.
• Mature extracellular elastin is highly insoluble, stable, and exhibits random coil conformations, allowing it to stretch and recoil during its physiological functions.
• Elastin degradation is catalyzed by neutrophil elastase, which can lead to destruction of alveolar walls and is clinically important in emphysema.
• Treatment of α1-antitrypsin deficiency, which can lead to emphysema, can include the infusion of recombinant α1-antitrypsin.
• α-Keratins are tough fibers found in hair, nails, and the outer epidermal layer of mammals, resistant to stretching due to their α-helical polypeptide structure and disulfide bridges.
• α-Keratins are resistant to stretching under normal conditions but can be affected by moist and heat conditions, causing changes in their properties.