Collagen is an abundant protein responsible for retaining the structural support of cells in the human body. It accounts for 80% of the connections of the skin, and is shown to change during the aging process. Among the numerous medical and cosmetic applications of collagen, it remains of great interest to researchers today, because of the consequences posed when these proteins fail.
From the Greek word, kolla, collagen means "glue manufacturer" and
refers to
the ancient process of boiling the skin and sinews of horses and other
animals to make glue. Collagen adhesive was used by
Egyptians about 4,000 years ago, and Native Americans used it in bows
about 1,500 years ago. The oldest glue in the world, carbon-dated as
more than 8,000 years old, was found to be collagen—used as a
protective lining on rope baskets and embroidered fabrics, and to hold
utensils together; also in crisscross decorations on human skulls.[31]
Collagen normally converts to gelatin, but survived due to the dry
conditions. Animal glues are thermoplastic, softening again upon
reheating, and so they are still used in making musical instruments
such as fine violins and guitars, which may have to be reopened for
repairs—an application incompatible with tough, synthetic plastic
adhesives, which are permanent. Animal sinews and skins, including
leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by
less-toxic pentanedial and ethanedial) has been used to repair
experimental incisions in rabbit lungs.
Collagen is the major
insoluble
fibrous protein in the extracellular matrix and in connective tissue.
In fact, it is the single most abundant protein in the animal kingdom.
There are at least 16 types of collagen, but 80 – 90 percent of the
collagen in the body consists of types I, II, and III (Table 22-3).
These collagen molecules pack together to form long thin fibrils of
similar structure (see Figure 5-20). Type IV, in contrast, forms a
two-dimensional reticulum; several other types associate with
fibril-type collagen, linking them to each other or to other matrix
components. At one time it was thought that all collages were secreted
by fibroblasts in connective tissue, but we now know that numerous
epithelial cells make certain types of collages. The various collages
and the structures they form all serve the same purpose, to help
tissues withstand stretching.
Collagen biosynthesis and assembly
follows the normal pathway for a secreted protein (see Figure 17-13).
The collagen chains are synthesized as longer precursors called
procollagens; the growing peptide chains are co-translationally
transported into the lumen of the rough endoplasmic reticulum (ER). In
the ER, the procollagen chain undergoes a series of processing
reactions (Figure 22-14). First, as with other secreted proteins,
glycosylation of procollagen occurs in the rough ER and Golgi complex.
Galactose and glucose residues are added to hydroxylysine residues, and
long oligosaccharides are added to certain asparagine residues in the
C-terminal propeptide, a segment at the C-terminus of a procollagen
molecule that is absent from mature collagen. (The N-terminal end also
has a propeptide.) In addition, specific proline and lysine residues in
the middle of the chains are hydroxylated by membrane-bound
hydroxylases. Lastly, intrachain disulfide bonds between the N- and
C-terminal propeptide sequences align the three chains before the
triple helix forms in the ER. The central portions of the chains zipper
from C- to N-terminus to form the triple helix.
After processing and assembly of type I procollagen is
completed, it is secreted into the extracellular space. During or
following exocytosis,
extracellular enzymes, the procollagen peptidases, remove the
N-terminal and C-terminal propeptides. The resulting protein, often
called tropocollagen (or simply collagen), consists almost entirely of
a triple-stranded helix. Excision of both propeptides allows the
collagen molecules to polymerize into normal fibrils in the
extracellular space (see Figure 22-14). The potentially catastrophic
assembly of fibrils within the cell does not occur both because the
propeptides inhibit fibril formation and because lysyl oxidase, which
catalyzes formation of reactive aldehydes, is an extracellular enzyme
(see Figure 22-12). As noted above, these aldehydes spontaneously form
specific covalent cross-links between two triple-helical molecules,
which stabilizes the staggered array characteristic of collagen
molecules and contributes to fibril strength.
In the beginning, the human body is a disorganized pile of cells. What tells these cells to create an organ, form an eye or organize into brain tissue are proteins called fibroblast growth factors. Collagen fibroblasts not only grow skin, they heal skin torn by wounds or tissue sliced by surgery.
Suresh Kumar, an assistant professor of chemistry and biochemistry, studies these factors to better understand how they function - and what can go wrong. "Fibroblast growth factors can be a boon or a bane," Kumar said. "A normal cell knows when to stop growing, but a cancerous cell does not know when to stop growing."
One way to block cancer growth may be to inhibit fibroblast growth factors--the things that tell a cell to continue growing. The The millions of proteins found in a cell all have receptors for their destined functions, and fibroblast growth factors are no exception - they too must bind with the proteins inside the cell in order to function. Chemical signals allow these factors to find their receptors amidst the chaos. By understanding the signals between the receptor and the fibroblast growth factors, we would be able to intervene with that particular signa," Kumar said.
Kumar uses nuclear magnetic resonance spectroscopy to study the three-dimensional structures of the fibroblast growth factor protein in solution. Through our studies of these structures, we have developed molecules that may be the first generation of drugs that can block fibroblast growth factor receptors, possibly shutting down the uncontrolled cell growth that characterizes cancer.
"Sometimes we want to block FGF. But sometimes we want to support its stability," Kumar said. In the case of healing wounds, for instance, it would be helpful to have fibroblast growth factors work fast and efficiently. To increase the efficiency of fibroblast growth factors, researchers have to understand the route that it takes to reach receptors located on the outer surface of the cell membrane.
Studies in Kumar's group has shown that fibroblast growth signals follow unconventional routes to reach their corresponding receptors. The growth factor does not have a signal peptide, a set of amino acids that tells it where to go, yet it has to reach its receptor, Kumar said. "It's like forgetting to write the address on an envelope, but the letter gets there anyway," he said.
It appears that the fibroblast growth signals form a multi-protein complex that allows it to travel to its final destination, where it will promote cell growth. Kumar's group is now studying this complex to better understand its role in the vital healing process. This unusual pathway may turn out to be a model to understanding the unconventional secretion of other proteins that lack signal peptides.
Collagen is a subject of great interest today because it is the primary building block connecting the cells in the body. Collagen is to the human body what glue is to a model car.
This so called glue that makes up the connective tissue in the body is the substance responsible for many marvels in the medical industry as well. Reconstructive surgery on the skin is a medical breakthrough that has restored the self-esteem to fire victims, among other accident victims who lived a normal life thereafter.
As with any claims of this nature, there is a lot of controversy around the fact that collagen can have this particular effect.
Around 30% of bone is composed of organic compounds, of which 90 to 95% is collagen, the rest being non-collagenous proteins. Collagen is a fibrous protein which provides the bone with strength and flexibility, and is an important component of many other tissues, including skin and tendon. Individual collagen molecules contain three polypeptides of about 1000 amino acids per chain with a high glycine and hydroxyproline content. Bundles of these collagen molecules are arranged in fibrils with a molecular weight close to 97.1 Daltons. These fibrils are twisted into a right handed coil (fibre) with a total weight of between 95000 and 102 000 Daltons (Waterlow et al. 1978:512; Woodhead-Galloway 1980:1-3, 23; Garlick 1969:504; Smith et al. 1983:211-12). For the collagen fibre to fully mature a number of chemical bonds must form. These include hydrogen bonds involving hydroxyproline, which stabilise the helix, and cross linkages involving hydroxylysine and lysine, which stabilise the fibrillar structure (Smith et al. 1983:447). These processes occur throughout the growth and maturity of an individual, consequently the density and stability of the bone tends to increase while the solubility decreases (Waterlow et al. 1978:512-14; Hare 1980:209; Smith et al. 1983:450). Once these bonds form only a small fraction of collagen can be extracted by neutral salt solutions and organic acids or acid-citrate buffers. The insoluble collagen which remains from such dissolutions, can however, be solubilised by heating above 58'C. At this temperature the triple helix denatures, but will partly reform into a gel when cooled (Waterlow et al. 1978:512; Woodhead-Galloway 1980:55; Smith et al. 1983:215). Collagen in its unaltered state is also very resistant to proteolytic enzymes, however a group of enzymes exist which degrade native collagen fibrils under physiological conditions of temperature and pH; these are the collagenases (Waterlow 1978:516; Smith et al. 1983:223). An enzyme secreted by the gas gangrene bacteria (Clostridium perfringens and Cl. histolyticum) and Bacteroides melaninogenicus, a bacterium common in the gingival crevice of the tooth, will also cleave the triple helix (Woodhead-Galloway 1980:59). The peptide's produced in such cleavage are then open to proteolytic attack from the more conventional enzymes (Waterlow 1978:516).