Structural Heterogeneity of Type I Collagen Triple Helix and Its Role in Osteogenesis Imperfecta

Makareeva, Elena; Mertz, Edward L.; Kuznetsova, Natalia V.; Sutter, Mary Beth; DeRidder, Angela; Cabral, Wayne A.; Barnes, Aileen M.; McBride, Daniel J.; Marini, Joan C.; Leikin, Sergey

doi:10.1074/jbc.m705773200

Cited by 82 publications

(103 citation statements)

References 53 publications

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“…Type I collagen, the most abundant collagen in cornea (11), is composed of three polypeptide chains and two types of single chains, ␣ 1 and ␣ 2 , both of which are accessible to polymerization through intra-and intermolecular bonds (58). Dimers of ␣ chains are called ␤-components (composed of ␣ 1 ␣ 2 or ␣ 1 ␣ 1 chains).…”

Section: Discussionmentioning

confidence: 99%

Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking

Zhang

Conrad

2011

Journal of Biological Chemistry

154

112

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Corneal cross-linking using riboflavin and ultraviolet-A (RFUVA) is a clinical treatment targeting the stroma in progressive keratoconus. The stroma contains keratocan, lumican, mimecan, and decorin, core proteins of major proteoglycans (PGs) that bind collagen fibrils, playing important roles in stromal transparency. Here, a model reaction system using purified, non-glycosylated PG core proteins in solution in vitro has been compared with reactions inside an intact cornea, ex vivo, revealing effects of RFUVA on interactions between PGs and collagen cross-linking. Irradiation with UVA and riboflavin cross-links collagen ␣ and ␤ chains into larger polymers. In addition, RFUVA cross-links PG core proteins, forming higher molecular weight polymers. When collagen type I is mixed with individual purified, non-glycosylated PG core proteins in solution in vitro and subjected to RFUVA, both keratocan and lumican strongly inhibit collagen cross-linking. However, mimecan and decorin do not inhibit but instead form cross-links with collagen, forming new high molecular weight polymers. In contrast, corneal glycosaminoglycans, keratan sulfate and chondroitin sulfate, in isolation from their core proteins, are not cross-linked by RFUVA and do not form cross-links with collagen. Significantly, when RFUVA is conducted on intact corneas ex vivo, both keratocan and lumican, in their natively glycosylated form, do form cross-links with collagen. Thus, RFUVA causes cross-linking of collagen molecules among themselves and PG core proteins among themselves, together with limited linkages between collagen and keratocan, lumican, mimecan, and decorin. RFUVA as a diagnostic tool reveals that keratocan and lumican core proteins interact with collagen very differently than do mimecan and decorin.The cornea is the transparent, dome-shaped tissue covering the front of the eye. It is a powerful refracting surface, providing 65-75% of the eye's focusing power, and is made up of three distinct layers: epithelium, stroma, and endothelium. The stroma comprises about 90% of cornea thickness in humans (1).Although it is very highly innervated, it does not contain any blood vessels (2-4). Collagen gives the cornea its strength, elasticity, and form (5). The unique molecular shape, paracrystalline arrangement, and very regular fine diameter of the evenly spaced collagen fibrils are essential in producing a transparent cornea (6, 7).In the corneal stromal extracellular matrix, glycosaminoglycan (GAG) 2 polysaccharides are the most abundant negatively charged macromolecules and are classified on the basis of their repeating disaccharide structures into four main groups: keratan sulfate (KS), chondroitin sulfate/dermatan sulfate (CS/DS), heparan sulfate and heparin, and hyaluronan. Glycosaminoglycans, normally covalently attached to proteoglycan (PG) core proteins, play important roles in corneal transparency, nerve growth cone guidance, and cell adhesion, largely dependent on their patterns of sulfation or lack of it (8, 9). The corneal stroma is comp...

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Section: Discussionmentioning

confidence: 99%

Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking

Zhang

Conrad

2011

Journal of Biological Chemistry

154

112

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“…Other factors suggested to contribute to clinical phenotype include the rigidity of its immediate sequence environment; its location with respect to the C terminus; its proximity to salt bridges; and its presence at an interaction site, such as the binding site for proteoglycans on collagen fibrils (7,9). A recent study of the stability of OI collagens supported the importance of the domain location of the mutation (10), whereas a network analysis of the mutations suggested the importance of a destabilizing tripeptide sequence C-terminal to the mutation site (11).…”

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confidence: 95%

“…It has not proved possible to obtain molecular information for the long collagen molecules themselves, but model collagen peptides have proved amenable to x-ray crystallography and NMR techniques (12,13). The structure of a peptide containing a Gly to Ala substitution near the center of the peptide (Pro-Hyp-Gly) 10 has been solved by x-ray crystallography (5). This structure shows an overall straight molecule with standard triple helical structures at both ends and a localized conformational deformation at the Ala replacement site.…”

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confidence: 99%

NMR Conformational and Dynamic Consequences of a Gly to Ser Substitution in an Osteogenesis Imperfecta Collagen Model Peptide

Brodsky²,

Baum

2009

Journal of Biological Chemistry

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Close packing of three chains in a standard collagen triple helix requires Gly as every third residue. Missense mutations replacing one Gly by a larger residue in the tripeptide repeating sequence in type I collagen are common molecular causes of osteogenesis imperfecta. The structural and dynamic consequences of such mutations are addressed here by NMR studies on a peptide with a Gly-to-Ser substitution within an ␣1(I) sequence. Distances derived from nuclear Overhauser effects indicate that the three Ser residues are still packed in the center of the triple helix and that the standard 1-residue stagger is maintained. NMR dynamics using H-exchange and temperature-dependent amide chemical shifts indicate a greater disruption of hydrogen bonding and/or increased conformational flexibility C-terminal to the Ser site when compared with N terminal. This is consistent with recent suggestions relating clinical severity with an asymmetric effect of residues N-versus C-terminal to a mutation site. Dynamic studies also indicate that the relative position between a Gly in one chain and the mutation site in a neighboring staggered chain influences the disruption of the standard hydrogen-bonding pattern. The structural and dynamic alterations reported here may play a role in the etiology of osteogenesis imperfecta by affecting collagen secretion or interactions with other matrix molecules.Mutations in collagen result in a variety of connective tissue diseases (1, 2), with the clinical phenotype depending on the location and function of the collagen type. For instance, mutations in type I collagen, the major collagen in bone, lead to a bone disorder, osteogenesis imperfecta (OI), 3 whereas mutations in type III collagen, which is present in high amounts in blood vessels, lead to aortic rupture in Ehlers-Danlos syndrome type IV (1, 2). All collagens have a triple helix motif composed of three polyproline II-like chains that are staggered by 1 residue and supercoiled about a common axis. The smallest residue Gly is typically present as every 3rd residue in each chain because of the tight packing of the chains, which generates the characteristic (Gly-Xaa-Yaa) n repeating sequence. The Gly residues are all buried in the center, and the structure is stabilized by interchain N-H (Gly) . . . CϭO (Xaa) hydrogen bonds (3-5). The most common type of mutation leading to collagen disorders is a missense mutation that replaces 1 Gly in the repeating sequence by a larger residue.The best characterized collagen disease is OI, or brittle bone disease, which is distinguished by fragile bones due to mutations in type I collagen (2, 6). More than 400 Gly substitution missense mutations in the ␣1(I) and ␣2(I) chains of type I collagen have been reported to lead to OI (7). The severity of the disease varies widely from mild cases with multiple fractures to perinatal lethal cases (2, 6, 7). A single base change in a Gly codon can lead to one of 8 residues (Ser, Ala, Cys, Val, Arg, Asp, Glu, Trp) or a missense mutation. The smallest residue Ala is...

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“…Recently, activation energies of local helix unfolding calculated from the host-guest triple-helix peptide data were found to be correlated with the decrease in T m values observed for 41 different Gly substitutions in OI collagens. 48 …”

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confidence: 99%

Triple‐helical peptides: An approach to collagen conformation, stability, and self‐association

et al. 2008

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Peptides have been an integral part of the collagen triple‐helix structure story, and have continued to serve as useful models for biophysical studies and for establishing biologically important sequence‐structure‐function relationships. High resolution structures of triple‐helical peptides have confirmed the basic Ramachandran triple‐helix model and provided new insights into the hydration, hydrogen bonding, and sequence dependent helical parameters in collagen. The dependence of collagen triple‐helix stability on the residues in its (Gly‐X‐Y)n repeating sequence has been investigated by measuring melting temperatures of host‐guest peptides and an on‐line collagen stability calculator is now available. Although the presence of Gly as every third residue is essential for an undistorted structure, interruptions in the repeating (Gly‐X‐Y)n amino acid sequence pattern are found in the triple‐helical domains of all nonfibrillar collagens, and are likely to play a role in collagen binding and degradation. Peptide models indicate that small interruptions can be incorporated into a rod‐like triple‐helix with a highly localized effect, which perturbs hydrogen bonds and places the standard triple‐helices on both ends out of register. In contrast to natural interruptions, missense mutations which replace one Gly in a triple‐helix domain by a larger residue have pathological consequences, and studies on peptides containing such Gly substitutions clarify their effect on conformation, stability, and folding. Recent studies suggest peptides may also be useful in defining the basic principles of collagen self‐association to the supramolecular structures found in tissues. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 345–353, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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Structural Heterogeneity of Type I Collagen Triple Helix and Its Role in Osteogenesis Imperfecta

Cited by 82 publications

References 53 publications

Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking

Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking

NMR Conformational and Dynamic Consequences of a Gly to Ser Substitution in an Osteogenesis Imperfecta Collagen Model Peptide

Triple‐helical peptides: An approach to collagen conformation, stability, and self‐association

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