Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Bodian, Dale L.; Madhan, Balaraman; Brodsky, Barbara; Klein, Teri E.

doi:10.1021/bi800026k

Cited by 68 publications

(83 citation statements)

References 32 publications

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Section: Discussionmentioning

confidence: 99%

“…A recent computational study has focused on the asymmetric influence of tripeptides flanking a Gly to Ser mutation site, noting that a destabilizing triplet C-terminal to a Gly to Ser substitution is correlated with a lethal OI phenotype, whereas no correlation is seen for an N-terminal destabilizing triplet (11). Consistent with this result, peptide studies showed a greater destabilization effect when a tripeptide of low triple helix propensity is put on the C-terminal side when compared with the N-terminal side of a Gly to Ser substitution (11). The NMR dynamic studies presented here on the T1-898(G901S) peptide suggest an inherent asymmetry surrounding a mutation site with less regular hydrogen bonding or increased conformational flexibility on the C-terminal side, and this inherent effect could be synergistic with the sequence-dependent stability of neighboring triplets.…”

Section: Discussionmentioning

confidence: 99%

“…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: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…The database has been used in the development of a model for predicting clinical lethality of mutations resulting in replacement of glycine with serine in type I collagen, which provided insight into the etiology of osteogenesis imperfecta [Bodian et al, 2008]. Analysis of the collected data also revealed that most Arg-Cys substitutions within the triple helical domains of the chains of type I collagen are colocated in a narrow region of the fibril overlapping band ''e'' in the gap zone (unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…Nucleotide data are provided as custom tracks for display in the UCSC genome browser [Kent et al, 2002], which permits viewing of the collagen-specific information in the context of the wealth of genomic data available through this popular tool. Analysis of the integrated data can lead to insights into the function of native collagen molecules and the mechanisms by which sequence variations lead to disease [Bodian et al, 2008].…”

Section: Introductionmentioning

confidence: 99%

COLdb, a database linking genetic data to molecular function in fibrillar collagens

Bodian

Klein

2009

Hum. Mutat.

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Fibrillar collagens are ubiquitous proteins essential for the structural integrity of bones, skin, blood vessels, and other tissues. Mutations in collagen genes result in disorders including osteogenesis imperfecta, chondrodysplasias, and Ehlers-Danlos syndromes, but the molecular basis for the heterogeneity of clinical phenotypes is not well understood. A more complete understanding of the relationship between sequence and phenotype requires synthesis of multiple facets of collagen structure and function. To facilitate such an analysis, we developed COLdb, a freely available database integrating collagen biological and physicochemical properties with known variants. A Web-based, interactive, graphical user interface displays the data as annotations on the collagen protein sequences. Collagen gene-level data are provided as custom tracks for display in the UCSC genome browser. COLdb currently includes 35,582 data points spanning collagen types I, II, and III, and, importantly, users can add their own data to the display. The database is the first comprehensive integration of disparate functional information on the three major fibrillar collagens, and the first electronic collection of mutations in the COL2A1 gene. Hum Mutat 30,[946][947][948][949][950][951]

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In Vitro Mineralization of Collagen

2021

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certain sponges. [4] In this respect the most important minerals are probably those related to calcium ions (HAp) and silicon ions (amorphous silica). Although many other biominerals are known, such as calcium carbonate and magnetite (iron), these are not encountered with collagen in biological systems. Moreover, even though there is no record of collagen-based calcium carbonate skeletons, the first successful experiments for intrafibrillar mineralization of collagen were achieved for this mineral. [5] The mechanism of formation of calcium carbonate inside collagen, however, may have illuminated that of HAp and silica. The formation of minerals, whether crystalline or amorphous, in or around a collagen template is generally termed collagen mineralization (a misnomer as another compound crystallizes within collagen).The reasoning behind collagen mineralization in vitro is two-fold: 1) understanding the processes behind bone mineralization and 2) mimicking bone tissue via synthetic procedures. Although these are two very different aspects, these often go hand-in-hand. Hence, numerous studies, both in living and synthetic systems, were performed to investigate the processes involved in collagen mineralization. [6] In this paper, we deal with the mineralization of collagen with minerals of calcium and silicon and, to a much lesser extent, other minerals, like yttria-stabilized zirconia and combinations of silica and HAp. In Section 2, we first provide a detailed summary of the molecular structure of collagen type I, the collagen type of interest for mineralization purposes. We provide an overview of collagen-based hybrid materials in nature in Section 3. In Section 4, we first cover the in vitro efforts toward mineralization with calcium carbonate and calcium phosphate (Section 4.1), followed by in vitro silicification (Section 4.2). This section is concluded with mineralization with multiphase minerals and other minerals (Section 4.3). In Section 5, the work reviewed here is placed into perspective. We provide some comments on the mechanisms involved in collagen mineralization and end this section with some concluding remarks and prospects for further research. Collagen Type I General Introduction about CollagenCollagen is a ubiquitous protein in animals. Only among the vertebrates, already 28 different types of collagen can be found. [7] All collagen-containing supramolecular structures in an organism are formed by different types of collagen and Collagen mineralization is a biological process in many skeletal elements in the animal kingdom. Examples of these collagen-based skeletons are the siliceous spicules of glass sponges or the intrafibrillar hydroxyapatite platelets in vertebrates. The mineralization of collagen in vitro has gained interest for two reasons: understanding the processes behind bone formation and the synthesis of scaffolds for tissue engineering. In this paper, the efforts toward collagen mineralization in vitro are reviewed. First, general introduction toward collagen type I, the main compone...

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Predicting the Clinical Lethality of Osteogenesis Imperfecta from Collagen Glycine Mutations

Cited by 68 publications

References 32 publications

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

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

COLdb, a database linking genetic data to molecular function in fibrillar collagens

In Vitro Mineralization of Collagen

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