Stabilization of the Collagen Triple Helix by<i>O</i>-Methylation of Hydroxyproline Residues

Kotch, Frank W.; Guzei, Ilia A.; Raines, Ronald T.

doi:10.1021/ja800225k

Cited by 130 publications

(139 citation statements)

References 29 publications

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“…This is in line with the presence of the dimer after photoexcitation at low energy, and might be linked to a stabilization of the triple helix model by the hydroxyprolines. Previously reported condensed phase experimental work lead to the same conclusion, indicating that this can be explained either by H-bonding between OH groups of hydroxyprolines and H 2 O molecules 40 , or by stereoelectronic effects tightening the triple helix structure 5 . The fact that our gas phase experiments on the same system also point to a stabilization supports the second hypothesis.…”

supporting

confidence: 53%

“…Many studies have been devoted to the triple helix stability and assembly in various solvents as well as to the design of collagen mimetic peptides 2,3 . In particular, the peptides (PPG) 10 and (PHypG) 10 are widely used triple helix models (P: proline, Hyp: hydroxyproline, G: glycine), with Hyp significantly increasing the thermal stability of the helix in solution 4,5 . UV irradiation of collagen and triple-helix models has been performed in solution, showing that the radicals created cause significant and specific cleavage of Gly-Pro peptide bonds, accompanied by transition from helical to random coil conformations [6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

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Single-photon absorption of isolated collagen mimetic peptides and triple-helix models in the VUV-X energy range

Schwob

Lalande

Rangama

et al. 2017

Phys. Chem. Chem. Phys.

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(2017). Single-photon absorption of isolated collagen mimetic peptides and triple-helix models in the VUV-X energy range. Physical Chemistry Chemical Physics, 19(28) Cartilage and tendons owe their special mechanical properties to the fibrous collagen structure. These strong fibrils are aggregates of a sub-unit consisting of three collagen proteins wound around each other in a triple helix. Even though collagen is the most abundant protein in the human body, the response of this protein complex to ionizing radiation has never been studied. In this work, we probe the direct effects of VUV and soft X-ray photons on isolated models of the collagen triple helix, by coupling a tandem mass spectrometer to a synchrotron beamline. Single-photon absorption is found to induce electronic excitation, ionization and conversion into internal energy leading to inter-and intra-molecular fragmentation, mainly due to Gly-Pro peptide bond cleavages. Our results indicate that increasing the photon energy from 14 to 22 eV reduces fragmentation. We explain this surprising behavior by a smooth transition from excitation to ionization occurring with increasing photon energy. Moreover, our data support the assumption of a stabilization of the triple helix models by proline hydroxylation via intra-complex stereoelectronic effects, instead of the influence of solvent.

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supporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Single-photon absorption of isolated collagen mimetic peptides and triple-helix models in the VUV-X energy range

Schwob

Lalande

Rangama

et al. 2017

Phys. Chem. Chem. Phys.

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“…Although we have used chemical synthesis, proline derivatives can be incorporated into proteins by heterologous expression by using proline auxotrophs of Escherichia coli or by semisynthetic methods (48)(49)(50)(51)(52)(53)(54). Derivatives other than 4-fluoroproline and 4-methylprolines can be used to bias ring pucker (55)(56)(57). The applicability is not limited to replacing proline residuesreplacing other residues with appropriate ϕ and ψ torsion angles (Table 3 and Table S1 in the SI Text) can also be beneficial.…”

Section: Resultsmentioning

confidence: 99%

Stereoelectronic and steric effects in side chains preorganize a protein main chain

Shoulders¹,

Satyshur²,

Forest³

et al. 2009

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

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152

142

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Preorganization is shown to endow a protein with extraordinary conformational stability. This preorganization is achieved by installing side-chain substituents that impose stereoelectronic and steric effects that restrict main-chain torsion angles. Replacing proline residues in ðProProGlyÞ 7 collagen strands with 4-fluoroproline and 4-methylproline leads to the most stable known triple helices, having T m values that are increased by >50°C. Differential scanning calorimetry data indicate an entropic basis to the hyperstability, as expected from an origin in preorganization. Structural data at a resolution of 1.21 Å reveal a prototypical triple helix with insignificant deviations to its main chain, even though 2∕3 of the residues are nonnatural. Thus, preorganization of a main chain by subtle changes to side chains can confer extraordinary conformational stability upon a protein without perturbing its structure.collagen triple helix | nonnatural amino acid | preorganization | protein stability | x-ray crystallography T he three-dimensional structures of proteins are stable because of a delicate balance of forces (1). Increases in the conformational stability of a protein-desirable in many contexts (2)-can be realized by enhancing the hydrophobic effect (3, 4), introducing or shielding a hydrogen bond (5) or electrostatic interaction (6-8), or introducing a disulfide crosslink (9-11) or metal ion-binding site (12). These strategies are often frustrated by enthalpy-entropy compensation, whereby enthalpic stabilization is offset entirely by entropic destabilization, or vice versa (13). Moreover, the strategies often lack subtlety and can lead to a misshapen and hence dysfunctional protein.As elaborated by Cram (14), the principle of preorganization states that, "the more highly hosts and guests are organized for binding and low solvation prior to their complexation, the more stable will be their complexes." In a typical manifestation, a conformational constraint is imposed upon a receptor or ligand during its chemical synthesis. This principle can also yield biopolymers with increased conformational stability (Fig. 1). For example, the stability of a DNA duplex correlates with the helicity of its single strands (15, 16), and a bicyclic ("locked") derivative of ribose enhances that stability (17, 18). The stability of β-turns within protein structures can be increased by incorporating Dproline (19) and certain β-amino acids (20) that bias the conformations occupied by the unfolded polypeptide. Likewise, proteins containing a cis-peptide bond can be stabilized by constrained amides or isosteres (21-23). The utility of these substitutions is limited, however, by the difficulty of modifying the backbone of proteins as well as concomitant effects on structure and function (24-27).We suspected that alterations to proline residues could provide a particularly incisive means to preorganize the conformation of a polypeptide chain. In classic work, Matthews and coworkers substituted proline, which is the least flexible residu...

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“…Proline derivatives bearing a substituent at the γ-carbon (C(4)) are an important tool in this respect since their s-cis:s-trans conformer ratios often differ from that of unsubstituted proline. [3,4] We became interested in (4R)-and (4S)-azidoproline (Azp) as versatile amino acids that allow for further functionalization. Our research started by utilizing the diketopiperazine 1R derived from (4R)Azp as a template for two-armed peptide receptors (Fig.…”

Section: Introductionmentioning

confidence: 99%

(4R)- and (4S)-Azidoprolines – Conformation Directing Amino Acids and Sites for Functionalization

Erdmann¹,

Kümin²,

Wennemers³

2009

Chimia

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An 'azido gauche effect' determines the conformation of (4S)-and (4R)-azidoproline (Azp) derivatives and affects the s-cis:s-trans conformer ratio of Xaa-Azp bonds. The article summarizes our research on the conformational analysis of monomers as well as oligomers derived from (4S)Azp and (4R)Azp. We show that (4S)Azp and (4R)Azp can be used to tune the stability of the polyproline II (PPII) helix. In addition we demonstrate that Azp containing oligoprolines are attractive molecular scaffolds with a well-defined helical conformation that can be readily further functionalized using e.g. click chemistry.

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Stabilization of the Collagen Triple Helix byO-Methylation of Hydroxyproline Residues

Cited by 130 publications

References 29 publications

Single-photon absorption of isolated collagen mimetic peptides and triple-helix models in the VUV-X energy range

Single-photon absorption of isolated collagen mimetic peptides and triple-helix models in the VUV-X energy range

Stereoelectronic and steric effects in side chains preorganize a protein main chain

(4R)- and (4S)-Azidoprolines – Conformation Directing Amino Acids and Sites for Functionalization

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