NMR Shows Hydrophobic Interactions Replace Glycine Packing in the Triple Helix at a Natural Break in the (Gly-X-Y) Repeat

Li, Yingjie; Brodsky, Barbara; Baum, Jean

doi:10.1074/jbc.m702910200

Cited by 33 publications

(76 citation statements)

References 33 publications

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“…[37][38][39] Peptides can form stable triple-helices in presence of interruptions which have 1, 4, or 6 amino acids between Gly residues, but the break leads to decreased stability, decreased triple-helix content, and decreased hydrogen bonding. The identity of the residue in the middle and the nature of the surrounding Gly-X-Y sequence affects the degree of destabilization for the smallest interruptions.…”

Section: Natural Interruptions In the Gly-x-y Repeating Pattern In Nomentioning

confidence: 99%

“…Interruptions with one or four amino acids between Gly residues show similar effects on the thermal stability and calorimetric enthalpy, and NMR and X-ray structures indicate that both can be incorporated into a straight triple-helix with a highly localized distortion that disrupts the register of the helix. [38][39][40] However, NMR studies show that in a peptide with a GlyPro-Hyp-Gly-Phe-Gly-Pro-Hyp interruption, the hydrophobic residue Phe is located on the outside of the helix 38 ( Figure 4a), while a peptide with the interruption Gly-ProHyp-Gly-Ala-Ala-Val-Met-Gly-Pro-Hyp has the hydrophobic Val residue located on the inside of the triple-helix, forming a small hydrophobic core in the center of triple-helix usually occupied by Gly (Figure 4b). 39 The disruption of the axial register of the triple-helix by such interruptions may …”

Section: Natural Interruptions In the Gly-x-y Repeating Pattern In Nomentioning

confidence: 99%

“…38,39 In (a), the cross-section view shows the Gly residues are closely packed at the center with the Phe residues on the outside, whereas in (b) the Val packs in the center at the position usually occupied by Gly, creating a small hydrophobic core. (c) View of the distribution of the eight interruptions present in human Type X collagen.…”

Section: Figurementioning

confidence: 99%

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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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Section: Natural Interruptions In the Gly-x-y Repeating Pattern In Nomentioning

confidence: 99%

Section: Natural Interruptions In the Gly-x-y Repeating Pattern In Nomentioning

confidence: 99%

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

et al. 2008

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“…Such peptides have been used to study the structure (6, 7), folding (8), and dynamics (9) of the triple helix. These peptides have been shown to retain the biochemical properties of the higher assemblies found in their natural counterparts, binding to cell surface proteins such as integrins (10).Most of the studies performed on collagen mimetic peptides utilize triple helices with three identical chains called homotrimers (8,(11)(12)(13). Such systems are good models for some types of collagen, like type II.…”

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confidence: 99%

“…Most of the studies performed on collagen mimetic peptides utilize triple helices with three identical chains called homotrimers (8,(11)(12)(13). Such systems are good models for some types of collagen, like type II.…”

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Solution Structure of an ABC Collagen Heterotrimer Reveals a Single-register Helix Stabilized by Electrostatic Interactions

Fallas

Gauba

Hartgerink

2009

Journal of Biological Chemistry

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Collagen, known for its structural role in tissues and also for its participation in the regulation of homeostatic and pathological processes in mammals, is assembled from triple helices that can be either homotrimers or heterotrimers. High resolution structural information for natural collagens has been difficult to obtain because of their size and the heterogeneity of their native environment. For this reason, peptides that self-assemble into collagen-like triple helices are used to gain insight into the structure, stability, and biochemistry of this important protein family. Although many of the most common collagens in humans are heterotrimers, almost all studies of collagen helices have been on homotrimers. Here we report the first structure of a collagen heterotrimer. Our structure, obtained by solution NMR, highlights the role of electrostatic interactions as stabilizing factors within the triple helical folding motif. This addresses an issue that has been actively researched because of the predominance of charged residues in the collagen family. We also find that it is possible to selectively form a collagen heterotrimer with a well defined composition and register of the peptide chains within the helix, based on information encoded solely in the collagenous domain. Globular domains are implicated in determining the composition of several collagen types, but it is unclear what their role in controlling register may be. We show that is possible to design peptides that not only selectively choose a composition but also a specific register without the assistance of other protein constructs. This mechanism may be used in nature as well.Collagens constitute an important structural protein family. They are found in the extracellular matrix and undergo a hierarchical self-assembly into large supramolecular structures with specific morphologies carefully crafted by nature to fulfill diverse structural and functional roles in a wide variety of tissues. In total, there are 28 known isoforms of collagen in humans arranged in a variety of structures and in a wide range of tissues. The feature defining this protein family is the presence of domains with uninterrupted Xaa-Yaa-Gly sequence repeats. These domains adopt a left-handed polyproline type II conformation because of the predominance of proline in the X position and hydroxyproline (Hyp ϭ O), a post-translationally modified amino acid with a hydroxyl group on the ␥-carbon of the proline side chain, in the Y position. Three such domains associate to form tightly packed right-handed triple helices in a folding motif commonly known as the collagen triple helix.Collagens are also implicated in pivotal homeostatic events in mammals such as the production of new vascular tissue and pathological conditions such as cancer metastasis (1). These processes are notoriously governed by interactions at the molecular level between cell surface proteins and the collagen triple helix and not by the morphology of the collagen aggregates (2, 3). Thus, an understanding of the colla...

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Molecular dynamic simulation studies on the effect of one residue chain staggering on the structure and stability of heterotrimeric collagen‐like peptides with interruption

et al. 2012

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A systematic molecular dynamics (MD) simulation has been carried out on collagen-like peptides with different combinations of interruptions in the Gly-X(AA) -Y(AA) repeats. Although experimental studies have been carried out to elucidate the structural consequences of homotrimeric collagen-like peptides, this is the first report on the structural effect on the heterotrimeric models with G4G and G1G breaks present simultaneously in the constituent chains with difference in one residue chain staggering. The results reveal that the axial registry of the interrupted region changes significantly from that of conventional triple helical peptide without interruption. Further, results from MD simulations show the formation of a kink in the interrupted region of the triple-helical peptides. The conformational analysis reveals that the interruption in the Gly-X(AA) -Y(AA) pattern in these peptides induces β-strand conformation in triple helical peptides. The conventional hydrogen bonds in the interrupted triad are affected and new nonconventional H-bonds are formed in the triple helical structure, and as a result interrupted region becomes locally fragile. MM-PBSA calculations on the different systems clearly suggest that the binding affinity varies marginally due to one residue staggering. However, it is found from the structural parameters that hydrogen-bonding pattern differs significantly due to the difference in the staggering of chains.

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NMR Shows Hydrophobic Interactions Replace Glycine Packing in the Triple Helix at a Natural Break in the (Gly-X-Y) Repeat

Cited by 33 publications

References 33 publications

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

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

Solution Structure of an ABC Collagen Heterotrimer Reveals a Single-register Helix Stabilized by Electrostatic Interactions

Molecular dynamic simulation studies on the effect of one residue chain staggering on the structure and stability of heterotrimeric collagen‐like peptides with interruption

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