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Collagen is the main protein of connective tissue in animals and the most abundant protein in mammals,[1] making up about 25% to 35% of the whole-body protein content. In muscle tissue it serves as a major component of endomysium. Collagen constitutes 1% to 2% of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles.[2] The gelatin used in food and industry is derived from the partial hydrolysis of collagen. normal aging, dry skin, arthritis etc.) rather than just a protein deficiency. From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling the skin and sinews of horses and other animals to obtain 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.[4] 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.[5]

Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular proteins such as enzymes. Tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments, tendons, bone and skin. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging. It strengthens blood vessels and plays a role in tissue development. It is present in the cornea and lens of the eye in crystalline form. It is also used in cosmetic surgery and burns surgery. Hydrolyzed collagen can play an important role in weight management, as a protein, it can be advantageously used for its satiating power.

Medical uses
Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes. Some points of interest are: 1. when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and 2. most medical collagen is derived from young beef cattle (bovine) from certified BSE (Bovine spongiform encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil and New Zealand. 3. porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes. 4. alternatives using the patient’s own fat, hyaluronic acid or polyacrylamide gel are readily available. Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe burns. These collagens may be derived from

Industrial uses
If collagen is sufficiently hydrolyzed, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. random coils. This process describes the formation of gelatin, which is used in many foods, including flavored gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.[3] From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the essential amino acids in the proportions that the human body requires—they are not ’complete proteins’ (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary supplements claim that their products can improve skin and fingernail quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims. Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as


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Tropocollagen triple helix.


bovine, equine or porcine, and even human, sources and are sometimes used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances. Collagen is also sold commercially as a joint mobility supplement[6]. This lacks supportive research as the proteins would just be broken down into its base amino acids during digestion, and could go to a variety of places besides the joints depending upon need and DNA orders. Recently an alternative to animal-derived collagen has become available. Although expensive, this human collagen, derived from donor cadavers, placentas and aborted fetuses, may minimize the possibility of immune reactions. Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic makeup.[7]

Conformation and structure
Collagen structure is complex. Its conformation can be considered at the monomeric level (individual) collagen molecules and/or at its aggregate level, how the monomers are arranged i.e. their packing structure (fibrils, networks, etc.—see table below)[8].

History and background
The molecular and packing structures of collagen have eluded scientists for decades; the first evidence that it possess a regular structure at the molecular level was presented in the mid-1930s [9] [10]. Since that time many prominent scholars, including (but not limited to) Nobel laureate Crick, and Pauling, Rich, Yonath, Brodsky, Berman and Ramachandran concentrated on the conformation of the collagen monomer. Several competing models although correctly dealing with the conformation of each individual peptide chain, gave way to the triplehelical "Madras" model which provided an essentially correct model of the molecule’s quaternary structure [11][12][13] although this model still required some refinement [14][15][16][17]. The packing structure of collagen has not been defined to the same degree outside of the fibrillar collagen types, although it has been long known to be hexagonal or quasi-hexagonal [18][19][20]. As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is ‘sheet-like’ or microfibrillar.[21][22] Recently it was confirmed that the microfibrillar structure as described by Fraser, Miller, Wess (amongst others) was closest to the observed structure, although it over-simplified the topological progression of neighboring


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collagen molecules and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril[23]

helices spontaneously, without any intrachain hydrogen bonding. Because glycine is the smallest amino acid with no side-chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro—a lower concentration of them is required in animals such as fish, whose body temperatures are lower than most warm-blooded animals.

Molecular structure
The tropocollagen or "collagen molecule" is a subunit of larger collagen aggregates such as fibrils. It is approximately 300 nm long and 1.5 nm in diameter, made up of three polypeptide strands (called alpha peptides), each possessing the conformation of a left-handed helix (its name is not to be confused with the commonly occurring alpha helix, a right-handed structure). These three left-handed helices are twisted together into a righthanded coiled coil, a triple helix or "super helix", a cooperative quaternary structure stabilized by numerous hydrogen bonds. With type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed super-super-coil that is referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring microfibrils to a degree that might suggest that they are individually unstable although within collagen fibrils they are so well ordered as to be crystalline. A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these collagen subunits. The sequence often follows the pattern Gly-Pro-Y or Gly-X-Hyp, where X and Y may be any of various other amino acid residues. Proline or hydroxyproline constitute about 1/6 of the total sequence. With Glycine accounting for the 1/3 of the sequence, this means that approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GXY character of collagen alpha-peptides. This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala- with 10% serine—and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of their sequence. Chemically-reactive side groups are not needed in structural proteins as they are in enzymes and transport proteins, however collagen is not quite just a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its non-proline rich regions have cell or matrix association / regulation roles. The relatively high content of Proline and Hydroxyproline rings, with their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed

Fibrillar structure
The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the extracellular spaces of tissues[24][25]. In the fibrillar collagens, the molecules are staggered from each other by about 67nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains 4 and a fraction collagen molecules. This is because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section—called the “overlap” and a part containing only 4 molecules.[23] The triple-helices are also arranged in a hexagonal or quasi-hexagonal array in cross-section, in both the gap and overlap regions.[23][26]. There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils)[27]. Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players[28]. Collagen’s insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques (Electron Microscopy (EM) and Atomic Force Microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to better understanding the way in which collagen structure affects cell-cell and cell-matrix communication and how tissues are constructed in growth and repair, and changed in development and disease[29][30]. Collagen fibrils are semi-crystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.


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Collagen fibrils / aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) hydroxyapatite, Ca10(PO4)6 (OH)2with some phosphate. It is in this way that certain kinds of cartilage turn into bone. Type I collagen gives bone its tensile strength.


Types and associated disorders
Collagen occurs in many places throughout the body. There are more than 28 types of collagen described in literature. Over 90% of the collagen in the body, however, are of type I, II, III, and IV. • Collagen One: skin, tendon, vascular, ligature, organs, bone (main component of bone) • Collagen Two: cartilage (main component of cartilage) • Collagen Three: reticulate (main component of reticular fibers), commonly found alongside type I. • Collagen Four: forms bases of cell basement membrane Collagen diseases commonly arise from genetic defects that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes in the normal production of collagen. In addition to the above mentioned disorders, excessive deposition of collagen occurs in Scleroderma.

Action of lysyl oxidase (in French) glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor. • Hydroxyproline (Hyp), derived from proline. • Hydroxylysine, derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines have disaccharides attached to them. Cortisol stimulates degradation of amino acid from skin collagen.[32]

In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to stain the collagen in tissue samples. The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required. The best stain for use in differentiating collagen from other fibers is Masson’s trichrome stain.

Collagen I formation
Most collagen forms in a similar manner, but the following process is typical for type I: 1. Inside the cell 1. Three peptide chains are formed (2 alpha-1 and 1 alpha-2 chain) in ribosomes along the Rough Endoplasmic Reticulum (RER). These peptide chains (known as preprocollagen) have registration peptides on each end; and a signal peptide is also attached to each 2. Peptide chains are sent into the lumen of the RER 3. Signal Peptides are cleaved inside the RER and the chains are now known as procollagen 4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on Ascorbic Acid (Vitamin C) as a cofactor 5. Glycosylation of specific hydroxylated amino acid occurs 6. Triple helical structure is formed inside the RER 7. Procollagen is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis

Amino acids
Collagen has an unusual amino acid composition and sequence: • Glycine (Gly) is found at almost every third residue • Proline (Pro) makes up about 9% of collagen • Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to


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Type I Notes Gene(s) Disorders


This is the most abundant collagen of the human body. It is COL1A1, present in scar tissue, the end product when tissue heals by repair. COL1A2 It is found in tendons, skin, artery walls, the endomysium of myofibrils, fibrocartilage, and the organic part of bones and teeth. Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. COL2A1

osteogenesis imperfecta, Ehlers-Danlos Syndrome, Infantile cortical hyperostosis aka Caffey’s disease Collagenopathy, types II and XI Ehlers-Danlos Syndrome


This is the collagen of granulation tissue, and is produced quickly COL3A1 by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber. Also found in artery walls, skin, intestines and the uterus basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6


Alport syndrome


most interstitial tissue, assoc. with type I, associated with placenta COL5A1, COL5A2, COL5A3 most interstitial tissue, assoc. with type I COL6A1, COL6A2, COL6A3 COL7A1 COL8A1, COL8A2 COL9A1, COL9A2, COL9A3 COL10A1 COL11A1, COL11A2 COL12A1

Ehlers-Danlos syndrome (Classical) Ulrich myopathy and Bethlem myopathy epidermolysis bullosa dystrophica - EDM2 and EDM3



forms anchoring fibrils in dermal epidermal junctions some endothelial cells FACIT collagen, cartilage, assoc. with type II and XI fibrils


hypertrophic and mineralizing cartilage cartilage FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans

Schmid metaphyseal dysplasia Collagenopathy, types II and XI -

transmembrane collagen, interacts with integrin a1b1, fibronectin COL13A1 and components of basement membranes like nidogen and perlecan. FACIT collagen transmembrane collagen, also known as BP180, a 180 kDa protein COL14A1 COL15A1 COL16A1 COL17A1


Bullous Pemphigoid and certain forms of junctional epidermolysis bullosa -


source of endostatin FACIT collagen



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XXVII XXVIII XXIX epidermal collagen

Atopic Dermatitis[31]

2. Outside the cell 1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase. 2. Multiple tropocollagen molecules form collagen fibrils, and multiple collagen fibrils form into collagen fibers 3. Collagen is attached to cell membranes via several types of protein, including fibronectin and integrin.

been preserved in dinosaur specimens dated as long ago as 80 million years ago.[36]


Synthetic pathogenesis
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal. Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval, expeditions during which participants were deprived of foods containing Vitamin C. In the human body, a malfunction of the immune system, called an autoimmune disease, results in an immune response in which healthy collagen fibers are systematically destroyed with inflammation of surrounding tissues. The resulting disease processes are called Lupus erythematosus, and rheumatoid arthritis, or collagen tissue disorders.[33] Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

Julian Voss-Andreae’s sculpture Unravelling Collagen (2005), stainless steel, height 11’3" (3.40 m). Julian Voss-Andreae has created sculptures based on the collagen structure out of bamboo and stainless steel. His piece "Unravelling Collagen" is, according to the artist, a "metaphor for aging and growth"[37][38].

Fossil record
Because the synthesis of collagen requires a high level of atmospheric oxygen, complex animals may not have been able to evolve until the atmosphere was oxygenic enough for collagen synthesis.[34] The origin of collagen may have allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very scarce.[35] There is mounting evidence—which remains controversial—that collagen has

See also
• Animal glue • Collagenase, the enzyme involved in collagen breakdown and remodelling. For more on other proteases that target collagen see The Proteolysis Map • Ehlers-Danlos Syndrome • Fibrous protein • Gelatine • Hypermobility Syndrome


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• • • • • • LOXL1 LOXL2 LOXL3 LOXL4 Marfan Syndrome Osteoid

[19] Jesior, J.C., A. Miller, and C. Berthet-Colominas, Crystalline three-dimensional packing is general characteristic of type I collagen fibrils. FEBS Lett, 1980. 113(2): p. 238–40. [20] Fraser, R.D.B. and T.P. MacRae, Unit cell and molecular connectivity in tendon collagen. Int. J. Biol. Macromol., 1981. 3: p. 193–200. [21] Fraser, R.D., T.P. MacRae, and A. Miller, Molecular packing in type I collagen fibrils. J Mol Biol, 1987. 193(1): p. 115–25. [22] Wess, T.J., et al., Molecular packing of type I collagen in tendon. J Mol Biol, 1998. 275(2): p. 255–67. [23] ^ Orgel, J.P., et al., "Microfibrillar structure of type I collagen in situ". Proc Natl Acad Sci U S A, 2006. 103(24): p. 9001–5. [24] Hulmes, D.J., Building collagen molecules, fibrils, and suprafibrillar structures. J Struct Biol, 2002. 137(1-2): p. 2–10 [25] Hulmes, D.J., The collagen superfamily—diverse structures and assemblies. Essays Biochem, 1992. 27: p. 49–67. [26] Hulmes, D.J. and A. Miller, Quasi-hexagonal molecular packing in collagen fibrils. Nature, 1979. 282(5741): p. 878-80. [27] Perumal, S., O. Antipova, and J.P. Orgel, Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis. Proc Natl Acad Sci U S A, 2008. 105(8): p. 2824–9. [28] Hulmes, D.J., The collagen superfamily—diverse structures and assemblies. Essays Biochem, 1992. 27: p. 49–67. [29] Sweeney, S.M., et al., Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J Biol Chem, 2008. 283(30): p. 21187–97. [30] Twardowski, T., et al., Type I collagen and collagen mimetics as angiogenesis promoting superpolymers. Curr Pharm Des, 2007. 13(35): p. 3608–21. [31] Söderhäll C, Marenholz I, Kerscher T, Rüschendorf F, Esparza-Gordillo J, et al., Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis. PLoS Biology Vol. 5, No. 9, e242 doi:10.1371/journal.pbio.0050242 [32] Houck, J.C.; Sharma, V.K.; Patel, Y.M.; Gladner, J.A. (1968) “Induction of Collagenolytic and Proteolytic Activities by AntiInflammatory Drugs in the Skin and Fibroblasts”. Biochemical Pharmacology 17: 2081, [33] AJR article about lupus and other collagen disorders [34] cambrian.htm

[1] Gloria A. Di LulloDagger , Shawn M. Sweeney, Jarmo Körkkö, Leena Ala-Kokko, and James D. San Antonio; Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen; J. Biol. Chem., Vol. 277, Issue 6, 4223-4231, February 8, 2002 Sikorski, Zdzisław E. (2001) Chemical and Functional Properties of Food Proteins. CRC Press. p. 242 Gelatin’s Advantages: Health, Nutrition and Safety Oldest Glue Discovered Ann Thorac Surg. 1994 Jun; 57(6): 1622–7 Hydrolyzed Collagen pills usages can-collagen-be-absorbed-into-the-skin-or-is-itall-just-one-big-hoax-674325.html Observe these structural aspect from a 3D perspective at molscilab/Jmol/collagen/collagen_index.htm Wyckoff, R., R. Corey, and J. Biscoe, X-ray reflections of long spacing from tendon. Science, 1935. 82: p. 175–176. Clark, G., Parker, E., Schaad, J. and Warren, W.J, New measurements of previously unknown large interplaner spaceings in natural materials. J. Amer. Chem. Soc, 1935. 57: p. 1509–1509. GNR — A Tribute - Resonance - October 2001 1689.pdf G.N. Ramachandran - Nature Structural & Molecular Biology Fraser, R.D., T.P. MacRae, and E. Suzuki, Chain conformation in the collagen molecule. J Mol Biol, 1979. 129(3): p. 463–81 Okuyama, K., et al., Crystal and molecular structure of a collagen-like polypeptide (Pro-Pro-Gly)10. J Mol Biol, 1981. 152(2): p. 427–43. Traub, W., A. Yonath, and D.M. Segal, On the molecular structure of collagen. Nature, 1969. 221(5184): p. 914–7. Bella, J., M. Eaton, B. Brodsky, and H.M. Berman, Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. Science, 1994. 266(5182): p. 75–81. Hulmes, D.J. and A. Miller, Quasi-hexagonal molecular packing in collagen fibrils. Nature, 1979. 282(5741): p. 878–80.

[2] [3] [4] [5] [6] [7]




[11] [12] [13] [14]






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[35] We, KENNETH M. TO (1996). "Fossil preservation in the Burgess Shale". Lethaia 29: 107. doi:10.1111/ j.1502-3931.1996.tb01844.x. edit [36] Schweitzer, M. H.; Wenxia Zheng,1 Chris L. Organ,3 Recep Avci,4 Zhiyong Suo,4 Lisa M. Freimark,5 Valerie S. Lebleu,6,7 Michael B. Duncan,6,7 Matthew G. Vander Heiden,8 John M. Neveu,9 William S. Lane,9 John S. Cottrell,10 John R. Horner,11 Lewis C. Cantley,5,12 Raghu Kalluri,6,7,13 John M. Asara5,14,* (2009). "Biomolecular Characterization and Protein Sequences of the Campanian Hadrosaur B. Canadensis". Science 324: 626. doi:10.1126/science.1165069. edit [37] Ward, Barbara (April 2006). "’Unraveling Collagen’ structure to be installed in Orange Memorial Park Sculpture Garden". Expert Rev. Proteomics 3 (2): 174. doi:10.1586/14789450.3.2.169. [38] Interview with J. Voss-Andreae "Seeing Below the Surface" in Seed Magazine


External links
• • • • • • • The Collagen Protein 12 types of collagen Database of type I and type III collagen mutations Science.dirbix Collagen Hydrolyzed Collagen Collagen Stability Calculator Computer-generated animations of the assembly of Type I and Type IV Collagens • Integrin-Collagen interface, PMAP (The Proteolysis Map)—animation • Integrin-Collagen binding model, PMAP (The Proteolysis Map)—animation • Collagen-Integrin atomic detail, PMAP (The Proteolysis Map)—animation

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