Collagen: The Body's Most Abundant Protein

If you could weigh every protein in your body separately, one would come out on top: collagen. It makes up roughly a quarter to a third of all the protein in the human body. It’s the main structural protein of skin, tendons, ligaments, bones, cartilage, blood vessels and the cornea of the eye. It’s also the reason jelly sets, why scurvy makes old wounds reopen, and why skin sags with age. All of this comes back to one unusual molecular structure.

A rope, not a ball

Many proteins you meet in biochemistry — enzymes, haemoglobin, antibodies — are globular: their chains fold into compact, roughly spherical shapes (see protein structure levels). Collagen is a fibrous protein. Its job is mechanical: to resist being pulled apart. Weight for weight, collagen fibres in tendons are remarkably strong in tension.

To get that strength, collagen uses a structure found in few other proteins: the triple helix.

The repeating sequence: Gly–X–Y

Collagen’s primary structure — its amino acid sequence — is strikingly repetitive. Along most of the chain, every third amino acid is glycine:

–Gly–X–Y–Gly–X–Y–Gly–X–Y–

X is very often proline and Y is often hydroxyproline, a modified form of proline. A single collagen chain (called an α chain) contains about 1,000 amino acids in this helical region, so the pattern repeats over 300 times.

Why glycine? Glycine is the smallest amino acid; its side chain is just a hydrogen atom (see amino acids). In the triple helix, three chains wind so tightly around each other that one position in every turn faces the crowded centre of the rope. Only glycine is small enough to fit there. Replace even one of those glycines with a bulkier amino acid and the helix is disrupted. This is exactly what happens in many cases of osteogenesis imperfecta (“brittle bone disease”), where a single change in the gene swaps a glycine for something larger.

Why proline? Proline’s side chain loops back and bonds to its own backbone nitrogen, forming a five-membered ring. This makes the chain rigid and forces a particular twist — a left-handed helix that is more extended than the familiar α-helix. The rigidity helps each chain hold its shape before it even meets its partners.

Three chains, one triple helix

Each collagen chain forms a left-handed helix. Three of these chains then wind around each other to form a right-handed triple helix, rather like the strands in a rope. The unit formed is called tropocollagen: a rod about 300 nm long and only about 1.5 nm wide.

What holds the three chains together? Mainly hydrogen bonds between the N–H group of each glycine and a C=O group on a neighbouring chain. Because the chains are so tightly packed, there’s a hydrogen bond at almost every turn. The alternating twist of the strands (left-handed in each chain, right-handed overall) also helps: when you pull on the rope, the twists tighten against each other rather than unwinding, just as in a braided rope.

Hydroxyproline and the role of vitamin C

Hydroxyproline isn’t built into the chain directly. The cell first makes collagen with ordinary proline, then an enzyme called prolyl hydroxylase adds an –OH group to certain prolines. Another enzyme does the same to some lysines, forming hydroxylysine.

These –OH groups stabilise the triple helix significantly; collagen without them falls apart at body temperature. And here’s the chemical link to nutrition: prolyl hydroxylase contains an iron ion in its active site, and it needs vitamin C (ascorbic acid) to keep that iron in the Fe²⁺ form. Without vitamin C, the enzyme gradually stops working (see vitamin C chemistry and cofactors and coenzymes).

That’s the chemistry behind scurvy. Sailors on long voyages without fresh fruit or vegetables developed bleeding gums, loose teeth, bruising and old wounds that reopened. Their bodies couldn’t make stable new collagen to replace what was constantly being broken down and renewed. In 1747, the naval surgeon James Lind ran one of the first controlled clinical trials, showing that sailors given citrus fruit recovered while those given other remedies did not.

From molecules to fibres: cross-links

Tropocollagen rods are secreted from cells and then line up side by side, staggered in a regular pattern, to form fibrils. This staggering produces the characteristic banded appearance, with a repeat of about 67 nm, seen under an electron microscope.

To turn fibrils into strong fibres, covalent cross-links form between neighbouring molecules. An enzyme called lysyl oxidase (which needs copper) converts some lysine and hydroxylysine side chains into reactive aldehydes. These react with other lysines on neighbouring molecules, bonding the rods together. It’s a bit like adding rungs between ropes in a net.

The amount and type of cross-linking changes with age. Young collagen is more easily renewed; older collagen gains more cross-links, including some formed by non-enzymatic reactions with sugars (glycation). This makes tissues stiffer and less elastic. Together with reduced production of new collagen, it’s one reason skin wrinkles and tendons become less springy with age. Ultraviolet light speeds the damage in skin by activating enzymes that break collagen down.

Different jobs, different collagens

Humans have about 28 types of collagen, coded by different genes. A few of the most important:

Type	Main locations	Notes
I	Skin, tendon, bone, cornea	The most abundant; thick, strong fibres
II	Cartilage	Thinner fibrils in a water-rich gel
III	Blood vessels, skin, internal organs	Often found alongside type I
IV	Basement membranes	Forms sheets, not fibres

In bone, type I collagen forms a scaffold on which crystals of a calcium phosphate mineral (hydroxyapatite) are deposited. The collagen provides flexibility and resistance to cracking; the mineral provides hardness. Take away the mineral (by soaking a bone in acid) and you get a flexible, rubbery bone; take away the collagen (by heating strongly) and you get a brittle one. More on the mineral side in calcium and bones.

Gelatin: collagen unravelled

When animal skin, bones and connective tissue are boiled for a long time, the triple helices unwind and many cross-links break. The single chains dissolve in hot water. This denatured, partly broken-down collagen is gelatin (see denaturation).

When a gelatin solution cools, the chains partly re-form short triple-helical sections that link neighbouring chains into a loose three-dimensional network. Water is trapped in the gaps and the liquid sets into a gel — jelly. Warm it up and the helices come apart again, so the gel melts. Gelatin gels melt a little below body temperature, which is part of why jelly “melts in the mouth”.

Fresh pineapple or kiwi fruit stops jelly from setting. They contain protease enzymes (bromelain and actinidin) that cut the gelatin chains into short fragments that can’t form a network. Tinned pineapple works fine, because heating during canning denatures the enzyme.

Do collagen supplements work?

Collagen powders and drinks are popular for skin, hair and joints. Chemically, eaten collagen is digested like any other protein, into amino acids and short peptides (see the chemistry of digestion). It doesn’t travel intact to your skin. Some studies suggest that certain collagen peptides may have modest effects, and research continues, but the evidence is mixed and many studies are small or industry-funded. What’s clear is that your body can build collagen from amino acids in any adequate protein diet, provided it also has enough vitamin C.

Common misconceptions

• “Collagen is one protein.” It’s a family of around 28 types with different structures and roles.
• “The triple helix is held together by covalent bonds.” The helix itself is held mainly by hydrogen bonds; covalent cross-links join separate molecules into fibres.
• “Vitamin C is part of collagen.” It isn’t built in; it keeps the hydroxylating enzyme’s iron active.
• “Gelatin is a different protein.” It’s collagen with its structure disrupted.

Key takeaways

• Collagen is the body’s most abundant protein and a fibrous structural protein.
• Its sequence repeats Gly–X–Y, often with proline and hydroxyproline; glycine fits the crowded centre.
• Three left-handed chains form a right-handed triple helix, held by hydrogen bonds; covalent cross-links join molecules into fibres.
• Vitamin C is needed to hydroxylate proline; its lack causes scurvy.
• Boiling turns collagen into gelatin, which forms a gel on cooling.

For another structural protein, read keratin: the chemistry of hair and nails.