Harpers

38 / CHAPTER 5to a particular organelle or facilitate its passage througha membrane. Others ensure that the potentially harmfulactivity of a protein such as the proteases trypsinand chymotrypsin remains inhibited until these proteinsreach their final destination. However, once thesetransient requirements are fulfilled, the now superfluouspeptide regions are removed by selective proteolysis.Other covalent modifications may take place thatadd new chemical functionalities to a protein. The maturationof collagen illustrates both of these processes.Collagen Is a Fibrous ProteinCollagen is the most abundant of the fibrous proteinsthat constitute more than 25% of the protein mass inthe human body. Other prominent fibrous proteins includekeratin and myosin. These proteins represent aprimary source of structural strength for cells (ie, thecytoskeleton) and tissues. Skin derives its strength andflexibility from a crisscrossed mesh of collagen and keratinfibers, while bones and teeth are buttressed by anunderlying network of collagen fibers analogous to thesteel strands in reinforced concrete. Collagen also ispresent in connective tissues such as ligaments and tendons.The high degree of tensile strength required tofulfill these structural roles requires elongated proteinscharacterized by repetitive amino acid sequences and aregular secondary structure.Collagen Forms a Unique Triple HelixTropocollagen consists of three fibers, each containingabout 1000 amino acids, bundled together in a uniqueconformation, the collagen triple helix (Figure 5–10). Amature collagen fiber forms an elongated rod with anaxial ratio of about 200. Three intertwined polypeptidestrands, which twist to the left, wrap around one anotherin a right-handed fashion to form the collagentriple helix. The opposing handedness of this superhelixand its component polypeptides makes the collagentriple helix highly resistant to unwinding—the sameprinciple used in the steel cables of suspension bridges.A collagen triple helix has 3.3 residues per turn and aAmino acidsequence – Gly – X – Y – Gly – X – Y – Gly – X – Y –2º structureTriple helixFigure 5–10. Primary, secondary, and tertiary structuresof collagen.rise per residue nearly twice that of an α helix. TheR groups of each polypeptide strand of the triple helixpack so closely that in order to fit, one must be glycine.Thus, every third amino acid residue in collagen is aglycine residue. Staggering of the three strands providesappropriate positioning of the requisite glycinesthroughout the helix. Collagen is also rich in prolineand hydroxyproline, yielding a repetitive Gly-X-Y pattern(Figure 5–10) in which Y generally is proline orhydroxyproline.Collagen triple helices are stabilized by hydrogenbonds between residues in different polypeptide chains.The hydroxyl groups of hydroxyprolyl residues also participatein interchain hydrogen bonding. Additionalstability is provided by covalent cross-links formed betweenmodified lysyl residues both within and betweenpolypeptide chains.Collagen Is Synthesized as aLarger PrecursorCollagen is initially synthesized as a larger precursorpolypeptide, procollagen. Numerous prolyl and lysylresidues of procollagen are hydroxylated by prolyl hydroxylaseand lysyl hydroxylase, enzymes that requireascorbic acid (vitamin C). Hydroxyprolyl and hydroxylysylresidues provide additional hydrogen bonding capabilitythat stabilizes the mature protein. In addition,glucosyl and galactosyl transferases attach glucosyl orgalactosyl residues to the hydroxyl groups of specifichydroxylysyl residues.The central portion of the precursor polypeptidethen associates with other molecules to form the characteristictriple helix. This process is accompanied bythe removal of the globular amino terminal and carboxylterminal extensions of the precursor polypeptideby selective proteolysis. Certain lysyl residues are modifiedby lysyl oxidase, a copper-containing protein thatconverts ε-amino groups to aldehydes. The aldehydescan either undergo an aldol condensation to form aC⎯C double bond or to form a Schiff base (eneimine)with the ε-amino group of an unmodified lysyl residue,which is subsequently reduced to form a C⎯N singlebond. These covalent bonds cross-link the individualpolypeptides and imbue the fiber with exceptionalstrength and rigidity.Nutritional & Genetic Disorders Can ImpairCollagen MaturationThe complex series of events in collagen maturationprovide a model that illustrates the biologic consequencesof incomplete polypeptide maturation. Thebest-known defect in collagen biosynthesis is scurvy, aresult of a dietary deficiency of vitamin C required by