The chemistry of the collagen cross-links. The mechanism of stabilization of the reducible intermediate cross-links

Robins, Simon P.; Bailey, Allen J.

doi:10.1042/bj1490381

Cited by 62 publications

(25 citation statements)

References 23 publications

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“…18). In certain cases, hydroxylation occurs in nonhelical peptides with sequences of X-Lys-Ala(Ser) at the end of collagen I chains that are involved in aldehyde-derived cross-links (19). This consensus sequence is identical to the X-Lys 211 -Ala sequence in the T-1414 peptide.…”

Section: Discussionmentioning

confidence: 83%

Identification of S-Hydroxylysyl-methionine as the Covalent Cross-link of the Noncollagenous (NC1) Hexamer of the α1α1α2 Collagen IV Network

Vanacore

Friedman

Ham

et al. 2005

Journal of Biological Chemistry

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Collagen IV networks are present in all metazoans as components of basement membranes that underlie epithelia. They are assembled by the oligomerization of triple-helical protomers, composed of three ␣-chains. The trimeric noncollagenous domains (NC1) of each protomer interact forming a hexamer structure. Upon exposure to acidic pH or denaturants, the hexamer dissociates into monomer and dimer subunits, the latter reflect distinct interactions that reinforce/cross-link the quaternary structure of hexamer. Recently, the crosslink site of the ␣1␣1␣2 network was identified, on the basis of x-ray crystal structures at 1.9-Å resolution, in which the side chains of Met 93 and Lys 211 were proposed to be connected by a novel thioether bond (Than, M. E., Henrich, S., Huber, R., Ries, A., Mann, K., Kuhn, K., Timpl, R., Bourenkov, G. P. Collagen IV networks are components of basement membranes that underlie epithelia, compartmentalize tissue, and influence cell behavior. The networks are assembled from a family of six polypeptide chains (␣1-␣6) that associate forming three subtypes of triple-helical protomers with distinct chain compositions: ␣1␣1␣2, ␣3␣4␣5, and ␣5␣5␣6 (1, 2). The protomers self-assemble by end-to-end associations in which the amino termini of four protomers associate tail-to-tail forming the 7 S domain, and the carboxyl termini of two protomers associate head-to-head through the noncollagenous (NC1) 1 domains, forming dimers. At the interface of the head-to-head connection, the trimeric NC1 domains exist as a hexamer, a stable complex that can be excised by cleavage with collagenase for in vitro studies.The NC1 domain plays a pivotal role in the assembly of the distinct collagen IV networks. In protomer assembly, the NC1 domains (monomers) of three chains interact, forming a NC1 trimer, to select and register chains for triple-helix formation. In the network assembly, the NC1 trimers of two protomers interact, forming a NC1 hexamer structure, to select and connect protomers. Upon exposure to acidic pH or denaturants, isolated NC1 hexamer dissociates into monomers and dimers, the latter reflecting the presence of cross-links that stabilize the trimer-trimer interface. The cross-links connect ␣1-like monomers (␣1-␣1, ␣1-␣5, and ␣3-␣5) and ␣2-like monomers (␣2-␣2, ␣2-␣6, and ␣4 -␣4) (3, 4). For two decades, the reduc- 1 The abbreviations used are: NC1, non-collagenous domain; PBM, placenta basement membrane; GdnHCl, guanidine hydrochloride; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; MS, mass spectrometry; LC-ESI/MS/MS and LC-ESI/MS 3 , liquid chromatography electrospray tandem mass spectrometry; HPLC, high performance liquid chromatography; DTT, dithiothreitol; Hyl, hydroxylysine; MS 3 , third fragmentation mass spectrometry.

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Section: Discussionmentioning

confidence: 83%

Identification of S-Hydroxylysyl-methionine as the Covalent Cross-link of the Noncollagenous (NC1) Hexamer of the α1α1α2 Collagen IV Network

Vanacore

Friedman

Ham

et al. 2005

Journal of Biological Chemistry

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“…Hydroxyproline values were used to calculate the amounts of crosslinks per collagen molecule (assuming 300 hydroxyproline residues per molecule). To identify the chemical nature of HLNL, the collected radioactive crosslink was subjected to Smith degradation (6)(7)33). The amounts of radiolabeled proline and lysine, which reflect the proportions of HLNL derived from the telopeptide Hyl or telopeptide lysine route, respectively, were measured chromatographically.…”

Section: Methodsmentioning

confidence: 99%

“…Normal amounts of HLNL were found; this crosslink can result from both telopeptidyl Lys and Hyl. To corroborate further that the telopeptides in BS contain little Hyl, the origin of HLNL was determined by Smith degradation (6)(7)33). The percentage of HLNL derived from hydroxylated telopeptides in BS was around 5%; in normal bone this is around 75%.…”

Section: Analysis Of Bs Bone Collagenmentioning

confidence: 99%

Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: Indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17

Bank

Robins

Wijmenga

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

177

165

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Bruck syndrome is characterized by the presence of osteoporosis, joint contractures, fragile bones, and short stature. We report that lysine residues within the telopeptides of collagen type I in bone are underhydroxylated, leading to aberrant crosslinking, but that the lysine residues in the triple helix are normally modified. In contrast to bone, cartilage and ligament show unaltered telopeptide hydroxylation as evidenced by normal patterns of crosslinking. The results provide compelling evidence that collagen crosslinking is regulated primarily by tissue-specific enzymes that hydroxylate only telopeptide lysine residues and not those destined for the helical portion of the molecule. This new family of enzymes appears to provide the primary regulation for controlling the different pathways of collagen crosslinking and explains why crosslink patterns are tissue specific and not related to a genetic collagen type. A genome screen identified only a single region on chromosome 17p12 where all affected sibs shared a cluster of haplotypes identical by descent; this might be the BS (Bruck syndrome) locus and consequently the region where bone telopeptidyl lysyl hydroxylase is located. Further knowledge of this enzyme has important implications for conditions where aberrant expression of telopeptide lysyl hydroxylase occurs, such as fibrosis and scar formation.Collagen fibrils are important for the mechanical strength of bone (1-2). The tensile properties of fibrils result from intermolecular crosslinks connecting the nonhelical ends of a collagen molecule (telopeptides) with the triple helical part of an adjacent molecule (2-3). More than ten different collagen crosslinks are known; their structure, number, and location are highly tissue specific and not related to a specific collagen type (4-8). Stereochemical and x-ray diffraction studies revealed that differences in molecular packing of collagen within fibrils are associated with differences in crosslink profiles (9-12). Proper mineralization probably depends on a correct alignment of collagen molecules, as nucleation of calcium apatite crystals starts in the gap region, i.e., in the area adjacent to the crosslink site (9). Alterations in crosslink patterns associated with changes in the molecular packing are, therefore, expected to result in aberrant mineralization.Residues involved in crosslinking are mainly the amino acids lysine (Lys) or hydroxylysine (Hyl) (4-8). The enzyme lysyl hydroxylase (LH) (procollagen-lysine, 2-oxoglutarate 5-dioxygenase; EC 1.14.11.4) catalyzes the conversion of Lys into Hyl (13-15). Crosslinking is initiated only after specific Lys or Hyl residues of the telopeptides are converted extracellularly by the enzyme lysyl oxidase into the aldehydes allysine and hydroxyallysine, respectively (4-8). The aldehydes subsequently react with Lys, Hyl, or histidyl, residues of the triple helix to give characteristic di-, tri-, and tetrafunctional crosslinks. Two related routes for the formation of crosslinks have been described, based on ...

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“…The reaction was stopped, and the products were reduced by adding 4M-NaOH and KB3H4 (2.5mg). After 30min the solution was adjusted to pH2.0 by the addition of 2M-HCI and the solution analysed for [3H]proline and [3H]lysine on the Locarte amino acid analyser (Robins & Bailey, 1975).…”

Section: Methodsmentioning

confidence: 99%

Chemistry of the collagen cross-links. Nature of the cross-links in the polymorphic forms of dermal collagen during development

Bailey

Sims

1976

Biochemical Journal

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Both the type I and type III collagens present in embryonic dermis are stabilized by the intermolecular cross-link, hydroxylysino-5-oxonorleucine, derived from hydroxylysinealdehyde, although the type I collagen possesses a significant proportion of dehydrohydroxylysinonorleucine. However, concurrent with the change in the proportion of the two types of collagen during postnatal development there is a change-over with both type I and III collagens to the labile cross-link, dehydrohydroxylysinonorleucine, derived from lysine aldehyde. The results indicate that the change in the nature of the cross-link with development is determined primarily by the change in the extent of hydroxylation of the lysine residues in the terminal non-helical regions rather than being due to the change in the type of collagen. (Epstein, 1974). Our own studies (Bailey & Robins, 1972) have demonstrated a corresponding change-over in the nature of the cross-links duri the early growth period from a stable intermolecular cross-link, derived from hydroxyallysine, to a chemically labile cross-link, derived from allysine. Therefor-we decided to demonstrate whether type III collagen also possesses lysine-derived cross-links in addition to its intramolecular disulphide bonds, and if so, whether there is a change in type of cross-link during development.In the present paper we report that such a change does occur in the nature of -the intermolecular cross-links of both types of collagen during the early growth period, thus confirming the previous preliminary results Ltd., Poole, Dorset, U.K. MethodsSkins were obtained from a 3-month foetal calf and a 9-month-old steer and were scraped clean of adhering fat, muscular tissue and the epidermis. The tissue was minced, and then extracted with M-NaCI/0.05M-Tris/HCl, pH7.5, for 2 days at 4°C. Separation of collagen types. Pepsin digestion and separation of type I and type III collagens were carried out as described by . Briefly, the insoluble residue from the salt (1 M-NaCI, pH7.4, 4°C for 2 days) and acid (0.5M-acetic acid, 4°C for 2 days) extractions was digested with pepsin at a substrate/enzyme ratio of 10:1 (w/w) for 19h at 5YC. After inactivation of the pepsin by raising the pH, the solubilized collagen was purified by precipitation with 5% (w/v) NaCi at 20°C, redissolved in 1 M-NaCl at 40C, and then subjected to fractional precipitation to obtain type III collagen at 1.6M-NaCl and type I collagen at 2.5M-NaCl.Sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. The type I and type III collagens were redissolved, denatured in sodium dodecyl sulphate (2 %, w/v) at 38°C and analysed for subunit composition by polyacrylamide-gel electrophoresis. The electrophoresis was carried out by using a flat-bed technique with 6.5 % (w/v) polyacrylamide gel, 211

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The chemistry of the collagen cross-links. The mechanism of stabilization of the reducible intermediate cross-links

Cited by 62 publications

References 23 publications

Identification of S-Hydroxylysyl-methionine as the Covalent Cross-link of the Noncollagenous (NC1) Hexamer of the α1α1α2 Collagen IV Network

Identification of S-Hydroxylysyl-methionine as the Covalent Cross-link of the Noncollagenous (NC1) Hexamer of the α1α1α2 Collagen IV Network

Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: Indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17

Chemistry of the collagen cross-links. Nature of the cross-links in the polymorphic forms of dermal collagen during development

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