Collagen

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Collagen, the most abundant protein in vertebrates, is an extracellular, inextensible fibrous protein that comprises the major protein component of such stress-bearing structures as bones, tendons, and ligaments. The objective of this exercise is to develop an understanding of the fibrous portion of collagen and to show how the different levels of protein structure come together and form a highly ordered and stable fiber. Collagen's properties of rigidity and inextensibility are due to this highly ordered structure. The non-structurally order part of collagen is not illustrated in this model. This part of the protein complex having a different amino acid composition, lysine and hydroxylysine are particularly important residues, is globular in nature and not as structurally organized. Lysine and hydroxylysine form covalent crosslinks in the protein complex, thereby adding strength and some flexibility to the fiber. This covalent crosslinking continues throughout life and produces rigid collagen and brittle bones in older adults. Links to additional general information and movies of assembly of triple helix of type I and IV collagen are available in the External Links section.

spinqualitylabelsall models Structure of Collagen (PDB entry 4CLG) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

spinqualitylabelsall models Collagen Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Structure of a SegmentStructure of a Segment

The collagen sequence is typically (Gly - Pro - hydroxy-Pro)_n.

Each forms an elongated left-handed helix. Three of these chains are associated to a right-handed .

Every third amino acid is

Ribbon and Spacefilling Diagrams of the Collagen Triple HelixRibbon and Spacefilling Diagrams of the Collagen Triple Helix

(KineMage currently not supported)

Fibrous proteins are, for the most part, characterized by highly repetitive simple sequences. We shall examine here a trimer that forms a collagen-like triple helix. Collagen, the most abundant protein in vertebrates, is an extracellular protein that comprises the major protein component of such stress-bearing structures as bones, tendons, and ligaments. Collagen is characterized by a distinctive repeating sequence: (Gly-X-Y)n where X is often Pro, Y is often 5-hydroxyproline (Hyp), and n may be >300. This, as we shall see, causes each collagen chain to assume a left-handed helical conformation with 3.3 residues per turn and a pitch (rise per turn) of 10.0 Å. Three such chains associate in parallel to form a right-handed triple helix.

Here we study a model compound for naturally occurring collagen, a 30-residue synthetic polypeptide of sequence (Pro-Hyp-Gly)4-Pro-Hyp-Ala-(Pro-Hyp-Gly)5, three chains of which associate to form a collagen-like triple helix of parallel strands that is 87 Å long and ~10 Å in diameter.

View1 shows the triple helical molecule in ribbon form seen perpendicular to its triple helical axis and with its three parallel and identical chains, "Chain 1", "Chain 2", and "Chain 3", colored purple, gold, and white, respectively. View2 is down the triple helical axis, a perspective in which this ribbon diagram appears to have a hollow center. However, click the "ANIMATE" button to show the spacefilling form and prove to yourself that the center is not hollow. Return to the ribbon diagram by clicking the "ANIMATE" button again before continuing.

Go back to View1 and repeatedly click the "2ANIMATE" button. This "grows" Strand 1 from its N- to its C-terminus in differently colored 3-residue increments. Note how the molecule's three strands twist around each other and that the triple helix makes one turn every ~7 three-residue repeats.

Repeatedly click the "ANIMATE" button to alternately display the original ribbon diagram and a spacefilling diagram of the polypeptide chains together with their side chains. The chains of the spacefilling diagram, which are colored identically to those of the ribbon diagram, can be individually turned on and off. Displaying one or two chains as ribbons and the remainder in spacefilling form may better reveal the helical character of the triple helix.

Collagen Backbone and the Effect of a MutationCollagen Backbone and the Effect of a Mutation

(KineMage currently not supported) This kinemage displays all of the atoms of the collagen model compound (Pro-Hyp-Gly)4-Pro-Hyp-Ala-(Pro-Hyp-Gly)5 in stick form (note that the "essential" Gly residue in this model compound's central triplet is replaced by Ala). View1 shows the triple helix in side view with "Chain 1" in pinktint, "Chain 2" in yellowtint, and "Chain 3" in white. The Pro, Hyp, and Ala side chains, which are independently controlled by the corresponding buttons, are green, cyan, and magenta, respectively. Use View1 and View2, which is down the triple helix axis, to prove to yourself that all Pro and Hyp side chains are on the periphery of the triple helix. These rigid groups are thought to help stabilize the collagen conformation.

View3 and View4 are side and top views of a segment of the collagen helix in which its three polypeptides all consist of repeating triplets of ideal sequence, (Gly-Pro-Hyp)n. Go to View3 to see that the three polypeptide chains are staggered in sequence by one residue, that is, a Gly on Chain 1 is at the same level along the triple helix axis as a Hyp on Chain 2 and a Pro on Chain 3. Turn on the "H bonds" button (H bonds are represented by dashed orange lines), to see that this staggered arrangement permits the formation of a hydrogen bond from the Gly main chain NH of Chain 1 to the Pro main chain O on Chain 2 (and likewise from Chain 2 to Chain 3 and from Chain 3 to Chain 1). Since the main chain N atoms of both Pro and Hyp residues lack H atoms, this exhausts the ability of the main chain to donate hydrogen bonds. Although the center of the triple helix appears to be hollow in View4, taking into account the van der Waals radii of its various atoms reveals that the center of the triple helix is, in fact, quite tightly packed. Indeed, the above hydrogen bonds pass very close to the center of the triple helix. This close packing accounts for the absolute requirement for a Gly at every third residue in a functional collagen molecule. Since, as you can see, the Gly Ca atoms are near the center of the triple helix, the side chain of any other residue at this position would, as we shall see below, significantly distort and hence destabilize the collagen triple helix.

View5 and View6 show the side and top views of the triple helix segment containing an Ala on each chain instead of a Gly. The effect of replacing the Gly H atom side chain with a methyl group to form Ala, the smallest residue substitution possible, is quite striking. The interior of the collagen triple helix is too crowded to accommodate an Ala side chain without significant distortion. The triple helix in this region therefore unwinds and expands so that no H-bonds form in this region. The unwinding of the triple helix in the region about the Ala residues is, perhaps, best seen by returning to KINEMAGE above this one. You can see that the triple helix is bulged out in the center of View1. These conformational changes, which disrupt collagen's rope-like structure, are responsible for the symptoms of such human diseases as osteogenesis imperfecta and certain Ehlers-Danlos syndromes.

Exercise in large part by John H. Connor (present address: Department of Microbiology, Boston University School of Medicine, 850 Harrison Ave, Boston, MA, 02118, USA)

The coordinates for the collagen-like polypeptide were obtained from 1CAG.

Additional InformationAdditional Information

See: Collagen Structure & Function for additional Information

Another Jmol tutorialAnother Jmol tutorial

Tutorial which illustrates and describes the 3D structure of collagen