Role of the amino‐terminal extrahelical region of type I collagen in directing the 4D overlap in fibrillogenesis

Abstract

SynopsisThe amino-terminal telopeptide of the collagen al(1) chain has a highly conserved sequence. This sequence was analyzed by the Chou-Fasman criteria, and a folded P-sheet conformation, including a P-turn, was predicted. This folded "hairpin" region favors both ionic and hydrophobic intermolecular interactions with al(1) chain residues 930-938 on a neighboring, end-overlapped molecule. An end-overlap interaction of this nature could direct the initial step in fibril formation. The predicted structure also places the potential crosslink-forming lysyl residue, gN, in a unique site a t the /3-turn end of the telopeptide.The type I collagen molecule exists as a long, stiff rod, 15 X 3000 A, composed of two identical al(1) chains and a nonidentical a2 chain. The al(1) chain is 1055 amino acids long; the characteristic triple-helix-forming sequence of repeating -Gly-X-Y-(where X is frequently proline and Y is frequently hydroxyproline) extends over the central 1014 residues.l Short non-triple-helix-forming sequences, called telopeptides,2 comprise the first 16 residues a t the amino terminal of al(1) chain and the last 25 residues at the carboxyl terminal. The telopeptides are rich in tyrosine, which does not occur in the triple-helical region. Each telopeptide contains a lysyl residue which is a potential crosslink precursor after enzymic oxidation to an aldehyde. The telopeptides are susceptible to several proteinases which cannot attack the triple-helical portion of the collagen m~l e c u l e .~-~ Interstitial collagen fibers exhibit a 670-w axial periodicity D, which has been measured both by x-ray diffraction and by electron microscopy. In the generally accepted two-dimensional repre~entation,~ each molecule, -4.40 in length, is displaced axially by 1D from each of its nearest neighbors, leaving an 0.6D gap between axially aligned molecules. The early four-strand6 and five-strand7 microfibril models, as well as more recent analyses,s-10 were designed to preserve the Hodge-Petruska 1D stagger in a three-dimensional ropelike array. The microfibril concept has received verification in small-and medium-angle x-ray diffraction studies of tendons'l and reconstituted collagen fibrils.12

Recombinant Procollagen II: Deletion of D Period Segments Identifies Sequences That Are Required for Helix Stabilization and Generates a Temperature-sensitive N-Proteinase Cleavage Site

“…A similar bent-back conformation was observed by rotary shadowing and electron microscopy of procollagen monomers (41). In addition, data on type I collagen from N-telopeptide binding studies (42,43), calculations of conformation (42)(43)(44), and peptide inhibitors of lysyl oxidase (45) indicated the N-terminal telopeptide is also folded into a bent-back conformation. Therefore, the bonds specifically cleaved by N-proteinase are probably exposed in a specific conformation.…”

Inhibition of the Self-assembly of Collagen I into Fibrils with Synthetic Peptides

“…Accordingly, there are several possible explanations for the observed binding of the N-telopeptides. One is that the binding occurs only with linear N-telopeptides such as those used here but not with N-telopeptides in the unusual hairpin conformation that is present in the native molecule (31)(32)(33)(34)(35) and that is essential both for assembly into well ordered fibrils and correct cross-linking (36). A second explanation is that binding of the N-telopeptides generates aberrant structural nuclei that cannot grow into fibrils and that resembles the "overshoot" struc- tures seen in the assembly of tobacco mosaic virus (37).…”

Collagen degradation products modulate matrix metalloproteinase expression in cultured articular chondrocytes

“…The enzyme is known to digest at multiple sites within the triple helix but leave the telopeptides intact, 15 in contrast to pepsin or pronase, which destroys the telopeptides but spares the triple helix. 16,17 In addition, a collagenase digest from whole articular collagen (colf, includes other collagen than type II, as well) was prepared from bovine knee cartilage. Finally, a 29-mer amino acid peptide was synthesized to correspond to the N-telo of human type II collagen.…”