Stability Junction at a Common Mutation Site in the Collagenous Domain of the Mannose Binding Lectin

Mohs, Angela; Li, Yingjie; Doss-Pepe, Ellen; Baum, Jean; Brodsky, Barbara

doi:10.1021/bi0482708

Cited by 10 publications

(11 citation statements)

References 41 publications

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“…1, A and B). Gly 28 , within the Gly-ProHyp repeating region at the C terminus, shows only a single trimer resonance at the typical position for Gly in standard triple helical peptides (14,30 , and Gly 19 , three trimer peaks are observed. It indicates that a well defined structure with three non-equivalent chains is present in the substitution region.…”

Section: Nmr Chain Assignments and Chemical Shifts Of The T1-898(g901s)mentioning

confidence: 95%

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: Nmr Chain Assignments and Chemical Shifts Of The T1-898(g901s)mentioning

confidence: 95%

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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“…189 The mutation occurs at a junction between highly ordered and weakly ordered helical regions, and thus the mutation is less destabilizing than Gly mutations observed in OI. 189 …”

Section: Structural Stability Studiesmentioning

confidence: 99%

Synthesis and biological applications of collagen-model triple-helical peptides

Fields¹

2010

Org. Biomol. Chem.

117

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Triple-helical peptides (THPs) have been utilized as collagen models since the 1960s. The original focus for THP-based research was to unravel the structural determinants of collagen. In the last two decades, virtually all aspects of collagen structural biochemistry have been explored with THP models. More specifically, secondary amino acid analogs have been incorporated into THPs to more fully understand the forces that stabilize triple-helical structure. Heterotrimeric THPs have been utilized to better appreciate the contributions of chain sequence diversity on collagen function. The role of collagen as a cell signaling protein has been dissected using THPs that represent ligands for specific receptors. The mechanisms of collagenolysis have been investigated using THP substrates and inhibitors. Finally, THPs have been developed for biomaterial applications. These aspects of THP-based research are overviewed herein.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Sequences of different lengths, ((Gly-Pro-Hyp) n ) 3 where n ) 1-10 systems were constructed. These are some of the model CPs synthesized in previous studies.…”

Section: Computational Detailsmentioning

confidence: 99%

“…These are some of the model CPs synthesized in previous studies. [11][12][13][14][15][16][17][18][19] Triple helical structures of each system were built using the gencollagen package, which is a tool used to generate the three-dimensional coordinates for the triple helical structure of collagen for a given sequence. 46 The model triple helical structures considered in this study were described schematically in Figure 1.…”

Section: Computational Detailsmentioning

confidence: 99%

“…These peptides have been characterized using circular dichrosim (CD) spectroscopy (at different temperatures), NMR spectroscopy, and X-ray diffraction techniques. [11][12][13][14][15][16][17][18][19] In this context, the group of Brodsky has made several noteworthy contributions on collagen stability and amino acid tendency to form collagen using model CPs. [20][21][22][23][24][25][26][27][28][29][30] From these studies, it is possible to derive the interrelationship between sequence, structure, stability, folding, and the propensity for various amino acids to adopt collagen-like conformations.…”

Section: Introductionmentioning

confidence: 99%

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Role of Length-Dependent Stability of Collagen-like Peptides

et al. 2008

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Understanding the structure, folding, and stability of collagen is complex because of its length and variations in the amino acid (AA) sequence composition. It is well known that the basic constituent of the collagen helix is the triplet repeating sequence of the form Gly-X(AA)-Y(AA). On the basis of previous models and with the frequency of occurrence of the triplets, the ((Gly-Pro-Hyp)n)3 (where n is the number of triplets) sequence replicate has been chosen as the model for the most stable form of the collagen-like sequence. With a view to understand the role of sequence length (or the number of triplets) on the stability of collagen, molecular dynamics simulations have been carried out by varying the number of triplet units on the model collagen-like peptides. The results reveal that five triplets are required to form the stable triple helix. Further analysis shows that the intermolecular structural rigidity of the imino acid residues, hydrogen bonding, and water structure around the three chains of the triple helix play the dominant roles on its structure, folding, and stabilization.

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Stability Junction at a Common Mutation Site in the Collagenous Domain of the Mannose Binding Lectin

Cited by 10 publications

References 41 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

Synthesis and biological applications of collagen-model triple-helical peptides

Role of Length-Dependent Stability of Collagen-like Peptides

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