COLLAGEN CHEMISTRY AND BIOLOGY COLLAGEN CHEMISTRY AND BIOLOGY DEFINITION: A protein with chains containing repetitive Gly-X-Y sequences allowing formation.

COLLAGEN CHEMISTRY AND BIOLOGY

DEFINITION:

A protein with chains containing repetitive Gly-X-Y sequences allowing formation of molecules with triple-helical domains.

The triple-helical domains as well as nontriple-helical domains of the molecules interact to form multimolecular aggregates that function primarily as structural elements in extracellular spaces.

Collagens are the most abundant protein in mammals (25% of protein mass).

Locations of Collagens (Skin)

Locations of Collagens (Basement Membranes)

LOCATIONS OF COLLAGEN (VASCULAR SYSTEM)

LOCATIONS OF COLLAGENS

BONESTEETHCARTILAGE

LOCATIONS OF COLLAGENS (TEETH)

LOCATIONS OF COLLAGENS (EYE)

Posterior Polymorphous Corneal Dystrophy

One cause is a dominantly acting mutation in a gene encoding for

collagen VIII (COL8A2). Ref: Coupal et al.

Osteogenesis imperfecta

Blue sclerae of an OI victimCaused by genetic mutations in

collagen genes COL1A1, COL1A2

COLLAGEN TYPES27 types with 45genetically distinct

chains:

1.Fiber-forming collagens: the quantitatively predominate collagenschains form several molecular species:

(Types I, II, III, V, and XI) + (XXIV and XXVII)

procollagen to collagen conversionfibers constructed of staggered, side to side,

parallel association of molecules

COLLAGEN TYPES, CONT.2. Fiber-associated collagens:

(IX, XII, XIV, XVI, XIX, XX, XXI, XXII)

3. Network collagens (IV, VIII, X)

4. Filament collagen (VI)

5. Anchoring fibril collagen (VII)

6. Transmembrane collagens:

(XIII, XVII, XXIII, XXV)

7. Multiplexins (XV, XVIII)

Characteristics: 1) smaller and often numerous helical domains;

2) procollagen to collagen conversion (seldom);

3) staggered, side to side and antiparallel association when aggregates are formed.

Collagens: primary structureAlmost every third residue is

glycineApprox 17% is prolineContains hydroxyprolineContains hydroxylysine (which

can form interchain bonds or be glycosylated)

Collagen – A Triple HelixPrincipal component of connective tissue

(tendons, cartilage, bones, teeth) Basic unit is tropocollagen:

◦ Three intertwined polypeptide chains (1K residues each)

◦ MW = 285,000 ◦ 300 nm long, 1.4 nm diameter ◦ Unique amino acid composition, including

hydroxylysine and hydroxyproline◦ Hydroxyproline is formed by the vitamin C-

dependent prolyl hydroxylase reaction.

Collagen – Hydroxylation of Proline

Scurvy (Vitamin C deficiency)

Scorbutic gums due to of scurvy. Notice gingival red triangles.

Vitamin C is needed for post translational amino acid modifications in collagen.

Collagen – A Triple Helix

The secrets of its a.a. composition...

Nearly one residue out of three is Gly

Proline content is unusually high Unusual amino acids found:

◦4-hydroxyproline ◦3-hydroxyproline ◦5-hydroxylysine ◦Pro and HyPro together make 30% of res.

A case of structure following composition

The unusual amino acid

composition of collagen is unsuited for alpha helices or beta sheets

It is ideally suited for the collagen triple helix: three intertwined helical strands

Much more extended than alpha helix, with a rise per residue of 2.9 Angstroms

3.3 residues per turn Long stretches of Gly-Pro-Pro/HyP

The Collagen Triple Helix

Collagen – A Triple Helix

Figure 6.16 Poly(Gly-Pro-Pro),a collagen-like right-handedtriple helix composed of threeleft-handed helical chains.

Staggered arrays of tropocollagens

Banding pattern in EMs with 68 nm repeat

Since tropocollagens are 300 nm long, there must be 40 nm gaps between adjacent tropocollagens (5 x 68 = 340 nm)

40 nm gaps are called "hole regions" - they contain carbohydrate and are thought to be nucleation sites for bone formation

Collagen Fibers

Collagen – A Triple Helix

Figure 6.17 In the electron microscope, collagen fibers exhibit alternating light and dark bands. The dark bands correspond to the 40-nm gaps between pairs of aligned collagen triple helices.

Every third residue faces the crowded center of the helix - only Gly fits here

Pro and HyP suit the constraints of φ and ψ

Interchain H-bonds involving HyP stabilize helix

Fibrils are further strengthened by intrachain lysine-lysine and interchain hydroxypyridinium crosslinks

Structural basis of the collagen triple helix

The hole regions of collagen fibrils may be the sites of nucleation for bone mineralization

A disaccharide of galactose and glucose is covalently linked to the 5-hydroxyl group of hydroxylysines in collagen by the combined action of galactosyltransferase and glucosyltransferase.

LYSYL HYDROXYLATION

MINERALIZATION

SYNTHESIS – ASSEMBLY OF A COLLAGEN MOLECULE

SPECIFICITY OF CHAIN ASSOCIATION

EXTRACELLLULAR PROCESSING OF COLLAGEN

FIBER ARCHITECTURE

CROSS-LINKS IN A FIBERPHYSICAL STABILITY

FIBROUS COLLAGEN SUMMARY

INDUSTRIAL AND CLINICAL USES OF COLLAGENDenatured collagen (gelatin): FOODS COATINGS CAPSULESNative collagen: SURGICAL DRESSINGS IMPLANTS TISSUE ENGINEERING

PREPARATION FOR CROSS-LINKING

REACTIONS FOR CROSS-LINKS