Anti aging

The Anatomy of Collagen Synthesis

Collagen, the most abundant protein in the body is predominantly synthesized   by fibroblasts; however, epithelial cells may also synthesize small amounts of   collagen. The collagen super family includes over 20 different types of collagen   with at least 38 distinct polypeptide chains. Of these types I, II, and III are   the most abundant and are involved in the formation of fibrils. Type IV collagen   forms a two-dimensional reticulum and is a major component of the basal lamina.   All collagens contain non-collagenous domains, which perform functions that are   distinct from those of the collagen domains. More recently, significant   attention has been focused on endostatin, a fragment released from type XVIII   collagen, which has been known to block angiogenesis and reduce tumor growth.

Collagens contain a Gly-X-Y repeating structure. The Glycine residue is   necessary in every third position to ensure close packaging. Although any amino   acid can be present at position X or Y, proline is more frequently found in the   X position and hydroxyproline in the Y position. Due to their ring structure,   both proline and hydroxyproline stabilize the helical conformation of   polypeptide chains. This triplet of amino acids allows collagen chains to twist   into a helical structure (a-helix) forming a super   helix. Each collagen molecule contains 3 chains twisted around each other to   form a triple helix. The 3 chains may either be identical or different depending   on the type of collagen. After collagens are secreted in the form of   pro-peptides, they are converted to collagen molecules by specific extracellular   proteolytic enzymes. The collagens then assemble in the extracellular space to   form collagen fibers. Collagen fibers strengthen and help in the organization of   the matrix, while elastin fibers provide structural flexibility

Collagens are synthesized as longer precursor proteins called procollagens.   Collagen fibers begin to assemble in the endoplasmic reticulum and Golgi  complexes. Here the signal sequence is removed and specific proline and lysine   residues are hydroxylated.  Prolyl hydroxylase converts proline residues to   hydroxyproline in the endoplasmic reticulum. Lysine residues in collagen are   also frequently converted to hydroxylysines by lysyl hydroxylase. The OH groups   of these modified amino acids help in stabilizing the collagen triple helix by   forming hydrogen bonds between polypeptide chains. Following completion of this   processing, procollagens are secreted into the extracellular space where   extracellular enzymes remove the pro-domain. The collagen molecules then   polymerize to form collagen fibrils. Oxidation of   specific lysine residues by lysyl oxidase forms reactive aldehydes that are   involved in the formation of specific cross-links between two chains. This   process helps in stabilizing collagens in the fibril. In type IV collagen, found   in basal lamina, the Gly-X-Y repeats are frequently interrupted by nonhelical   sequences that allow greater flexibility than seen in fibril-forming collagens.

The critical role of collagens is evident from a wide spectrum of diseases   resulting from hundreds of known mutations in 22 genes for 12 different collagen   types. Defects in the synthesis and degradation of collagen and elastin   contribute to a number of diseases. Some of the   well-known collagen related diseases include osteogenesis imperfecta, many   chondrodysplasias, some cases of osteoporosis, and several subtypes of the   Ehlers-Danlos syndromes. The adhesive proteins assist cells to attach to the   extracellular matrix. For example, fibronectin, a large dimeric glycoprotein,   promotes the attachment of fibroblasts and other cells to the matrix in   connective tissue. It interacts with a wide variety of proteins, including   collagen, heparin, fibrin, gelatin, DNA and cell-surface receptors of integrins.   Fibronectins can also regulate the shape of cells and organize cytoskeleton.   Fibronectins bind extracellular matrix proteins through a tripeptide   arginine-glycine-aspartic acid (RGD) sequence. By facilitating the   migration of immune cells to the site of injury fibronectins play an important   role in wound healing. They bind to integrins on platelets via RGD domains and   cause localization of platelets to the site of injury. They also bind to fibrin   and assist in blood clotting. Other adhesive molecules, such as laminin, promote   the attachment of epithelial cells to the basal lamina. Laminin is a hetrotrimer, consisting of A (400 kDa), B1 and B2 subunits (200 kDa each). Each   subunit contains at least 12 repeats of EGF-like domains. The number of EGF   repeats varies between different species. Laminin also stimulates spreading of   many cell types and promotes the outgrowth of neurites in culture.

Biochemical Characteristics of Major Types of Collagens and Their Distribution in Tissues & Cells

Collagen Types

  • Chains
  • Anchor
  • Cell Surface Receptor
  • Associated Proteoglycans
  • Localization in Tissues (and cells)
  • Fibronectin
  • Integrin
  • Chondroitin and dermatan sulfates
  • Skin, tendon, bone (fibroblasts)
  • Fibronectin
  • Integrin
  • Chondroitin sulfate
  • Cartilage, vitreous humor (chondrocytes)
  • Fibronectin
  • Integrin
  • Heparan sulfate and heparin

Skin, muscle, frequently found with type I collagen (quiescent   hepatocytes, epithelial; fibroblasts):

  • Laminin
  • Laminin receptors
  • Heparan sulfate and heparin
  • All basal lamina (all epithelial cells, endothelial cells, regenerating hepatocytes)

Glycosaminoglycans (GAGs) generally form a highly hydrated, gel-like   substance, in which fibrous proteins are embedded. GAGs are   heteropolysaccharides consisting of long unbranched polysaccharides containing a   repeating disaccharide unit. The disaccharide units contain either   N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) and an uronic   acid such as glucuronate or iduronate. GAGs are located either on the cell   surface or in ECM. They exhibit high degree of viscosity and low   compressibility, which makes them suitable for lubricating joints. The majority   of GAGs are linked to core proteins and form proteoglycans   (mucopolysaccharides). This linkage involves a specific trisaccharide consisting   of two galactose and a xylulose residue   (GAG-GalGalXyl-O-CH2-protein).

Aggrecan, a large aggregating chondroitin sulfate proteoglycan is found   mainly in cartilage. It may account for up to 10% of the dry weight of   cartilage. It is considered as a space-filling proteoglycan and its primary   function appears to maintain a high level of hydration in cartilage ECM.   Aggrecan is a monomer consisting of a protein backbone of 210 to 250 kDa to   which chondroitin sulfate and keratan sulfate are attached. Individual monomers   can interact with hyaluronic acid to form high molecular weight aggregates. The   presence of chondroitin sulfate chains on aggrecan helps in generating an   osmotic swelling pressure, which may result in up to 75% water content in the   articular cartilage. The osmotic swelling is primarily due to the   glycosaminoglycan chains attached to the aggrecan core. During the resting   phase, osmotic swelling is reported to be at its maximum. However, during   loading when body weight compresses the cartilage water is squeezed out. When   the load is removed and the compressive force is normalized maximum swelling is   restored.

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