Stabilization of the collagen structure by hydroxyproline residues (original) (raw)
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A hypothesis on the role of hydroxyproline in stabilizing collagen structure
Biochimica Et Biophysica Acta - Proteins And Proteomics, 1973
The possibility of hydroxyproline residues stabilizing the collagen triple-helical structure by the formation of additional hydrogen bonds through their ~-hydroxyl group has been studied from structural considerations. It is not possible for this hydroxyl group to form a direct hydrogen bond with a suitable group in a neighbouring chain of the triple-helical protofibril. However, in the modified one-bonded structure, which is stabilized by additional hydrogen bonds being formed through water molecules as intermediaries (put forward in 1968 by Ramachandran, G. N. and Chandrasekharan, R.), it is found that the 7-hydroxyl group of hydroxyproline can form a good hydrogen bond with the water oxygen as acceptor, the hydrogen bond length being 2.82 A. It is proposed that, in addition to stabilizing the collagen triple-helical structure due to the stereochemical properties of the pyrrolidine ring, hydroxyproline gives added stability by the formation of an extra hydrogen bond. Experimental studies on the determination of shrinkage and denaturation temperatures of native collagen and its synthetic analogues, as a function of their hydroxyproline content, are being undertaken to test this hypothesis.
Collagen Structure: The Madras Triple Helix and the Current Scenario
Iubmb Life, 2005
This year marks the 50th anniversary of the coiled-coil triple helical structure of collagen, first proposed by Ramachandran's group from Madras. The structure is unique among the protein secondary structures in that it requires a very specific tripeptide sequence repeat, with glycine being mandatory at every third position and readily accommodates the imino acids proline/ hydroxyproline, at the other two positions. The original structure was postulated to be stabilized by two interchain hydrogen bonds, per tripeptide. Subsequent modeling studies suggested that the triple helix is stabilized by one direct inter chain hydrogen bond as well as water mediated hydrogen bonds. The hydroxyproline residues were also implicated to play an important role in stabilizing the collagen fibres. Several high resolution crystal structures of oligopeptides related to collagen have been determined in the last ten years. Stability of synthetic mimics of collagen has also been extensively studied. These have confirmed the essential correctness of the coiledcoil triple helical structure of collagen, as well as the role of water and hydroxyproline residues, but also indicated additional sequencedependent features. This review discusses some of these recent results and their implications for collagen fiber formation.
Hydroxylation-induced Stabilization of the Collagen Triple Helix
Journal of Biological Chemistry, 2003
Xaa-Yaa-repeated sequence of collagen plays a crucial role in the stability of the triple helix. Since the peptide (4(R)-Hyp-Pro-Gly) 10 does not form a triple helix, it was generally believed that polypeptides with a-Gly-4(R)-Hyp-Yaa-repeated sequence do not form a triple helix. Recently, we found that acetyl-(Gly-4(R)-Hyp-Thr) 10-NH 2 forms a triple helix in aqueous solutions. To further study the role of 4(R)-hydroxyproline in the Xaa position, we made a series of acetyl-(Gly-4(R)-Hyp-Yaa) 10-NH 2 peptides where Yaa was alanine, serine, valine, and allo-threonine. We previously hypothesized that the hydroxyl group of threonine might form a hydrogen bond to the hydroxyl group of 4(R)hydroxyproline. In water, only the threonine-and the valine-containing peptides were triple helical. The remaining peptides did not form a triple helix in water. In 1,2-and in 1,3-propanediol at 4°C, all the soluble peptides were triple helical. From the transition temperature of the triple helices, it was found that among the examined residues, threonine was the most stable residue in the acetyl-(Gly-4(R)-Hyp-Yaa) 10-NH 2 peptide. The transition temperatures of the valine-and allo-threonine-containing peptides were 10 degrees lower than those of the threonine peptide. Surprisingly, the serine-containing peptide was the least stable. These results indicate that the stability of these peptides depends on the presence of a methyl group as well as the hydroxyl group and that the stereo configuration of the two groups is essential for the stability. In the threonine peptide, we hypothesize that the methyl group shields the interchain hydrogen bond between the glycine and the Xaa residue from water and that the hydroxyl groups of threonine and 4(R)hydroxyproline can form direct or water-mediated hydrogen bonds.
Characterization of collagen-like heterotrimers: Implications for triple-helix stability
Biopolymers, 2004
This article deals with the effects of proline hydroxylation on collagen triple-helix stability, an issue that is still under discussion. To investigate the structural determinants of triple-helix stabilization by hydroxyproline (Hyp), we here characterized spectroscopically triplehelix heterotrimers containing both chains of (Pro-Pro-Gly) 10 and (Pro-Hyp-Gly) . Results are discussed in relation to the various triple-helix stabilization mechanisms.
Collagen Structure and Stability
Collagen is the most abundant protein in animals. This fibrous, structural protein comprises a right-handed bundle of three parallel, lefthanded polyproline II-type helices. Much progress has been made in elucidating the structure of collagen triple helices and the physicochemical basis for their stability. New evidence demonstrates that stereoelectronic effects and preorganization play a key role in that stability. The fibrillar structure of type I collagen-the prototypical collagen fibrilhas been revealed in detail. Artificial collagen fibrils that display some properties of natural collagen fibrils are now accessible using chemical synthesis and self-assembly. A rapidly emerging understanding of the mechanical and structural properties of native collagen fibrils will guide further development of artificial collagenous materials for biomedicine and nanotechnology. 929 Annu. Rev. Biochem. 2009.78:929-958. Downloaded from arjournals.annualreviews.org by California Institute of Technology on 06/04/09. For personal use only.
Molecular stability of chemically modified collagen triple helices
FEBS Letters, 2003
Ionic residues in£uence the stability of collagen triple helices and play a relevant role in the spontaneous aggregation of ¢brillar collagens. Collagen types I and II and some of their CNBr peptides were chemically modi¢ed in mild conditions with two di¡erent protocols. Primary amino groups of Lys and Hyl were N-methylated by formaldehyde in reducing conditions or N-acetylated by sulfosuccinimidyl acetate. The positive charge of amino groups at physiological pH was maintained after the former modi¢cation, whereas it was lost after the latter. These chemical derivatizations did not signi¢cantly alter the stability of the triple helical conformation of peptide trimeric species. Also the enthalpic change on denaturation was largely unaffected by derivatizations. This implies that no signi¢cant variation of weak bonds, either in number or overall strength, and of entropy occur on modi¢cation. These properties can probably be explained by the fact that chemically modi¢ed groups maintain the ability to form hydrogen bonds. ß (R. Tenni).
Stabilization mechanism of triple helical structure of collagen molecules
2003
The role of 4-hydroxyproline (Hyp) in stabilizing collagen triple helical structure has been investigated comprehensively. Recently it was emphasized that the preferential pyrrolidine ring pucker influenced by the stereoelectronic effects of substituted groups mainly affects the thermal stability of the triple helix. To examine this explanation, we synthesized and characterized (fPro R-Pro-Gly) 10 and (fPro S-Pro-Gly) 10. According to the results of CD and analytical ultracentrifugation, (fPro S-Pro-Gly) 10 takes a triple helical structure and (fPro R-Pro-Gly) 10 exists in a single chain structure, the trend of which is not consistent with the relationship between (Hyp S-Pro-Gly) 10 and (Hyp R-Pro-Gly) 10. In order to rationalize experimental results as a whole, we carried out DSC analyses and determined the thermodynamic parameters associated with the structural transition of these collagen model peptides. In this paper, we reported the DSC results for (Pro-Pro-Gly) 10 , (Pro-Hyp R-Gly) 10 and (Pro-fPro R-Gly) 10 as a part of this study. Based on those parameters, we concluded that Hyp and fPro stabilize the triple helix in different stabilizing mechanisms; the increased stability of (Pro-Hyp R-Gly) 10 is ascribed primarily to the enthalpic effects while that of (Pro-fPro R-Gly) 10 is achieved through the entropic ones.
Ab initio and density functional theory based studies on collagen triplets
Theoretical Chemistry Accounts: Theory, Computation, and Modeling (Theoretica Chimica Acta), 2003
An understanding of the amino acid sequence dependent stability of polypeptides is of renowned interest to biophysicists and biochemists, in order to identify the nature of forces that stabilize the threedimensional structure of proteins. In this study, the role of various collagen triplets influencing the stability of collagen has been addressed. It is found from this study that proline can stabilize the collagen triplet only when other residues are also in the polyproline II conformation. Solvation studies of various triplets indicate that the presence of polar residues increases the free energy of solvation. Especially the triplets containing arginine residues displays a higher solvation free energy. The chemical hardness of all the triplets in collagen-like conformation has been found to be higher than that in the extended conformation. Studies on Gly-X-Y, Gly-X-Hyp, and Gly-Pro-Y triplets confirm that there will be local variations in the stability of collagen along the entire sequence.
Journal of Biological Chemistry, 2003
Hydroxylation of proline residues in the Yaa position of the Gly-Xaa-Yaa repeated sequence to 4(R)-hydroxyproline is essential for the formation of the collagen triple helix. A small number of 3(S)-hydroyxyproline residues are present in most collagens in the Xaa position. Neither the structural nor a biological role is known for 3(S)hydroxyproline. To characterize the structural role of 3(S)-hydroxyproline, the peptide Ac-(Gly-3(S)Hyp-4(R)Hyp) 10-NH 2 was synthesized and analyzed by circular dichroism spectroscopy, analytical ultracentrifugation, and 1 H nuclear magnetic resonance spectroscopy. At 4°C in water the circular dichroism spectrum indicates that this peptide was in a polyproline-II-like secondary structure with a positive peak at 225 nm similar to Ac-(Gly-Pro-4(R)Hyp) 10-NH 2. The positive peak at 225 nm almost linearly decreases with increasing temperature to 95°C without an obvious transition. Although the peptide Ac-(Gly-Pro-4(R)Hyp) 10-NH 2 forms a trimer at 10°C, sedimentation equilibrium experiments indicate that Ac-(Gly-3(S)Hyp-4(R)Hyp) 10-NH 2 is a monomer in water at 7°C. To study the role of 3(S)-hydroxyproline in the Yaa position, we synthesized Ac-(Gly-Pro-3(S)Hyp) 10-NH 2. This peptide also does not form a triple helix in water. 1 H Nuclear magnetic resonance spectroscopy data (including line widths and nuclear Overhauser effects) are entirely consistent, with neither Ac-(Gly-3(S)Hyp-4(R)Hyp) 10-NH 2 nor Ac-(Gly-Pro-3(S)Hyp) 10-NH 2 forming a triple helix in water. Therefore 3(S)-hydroxyproline destabilizes the collagen triple helix in either position. In contrast, when 3(S)-hydroxyproline is inserted as a guest in the highly stable-Gly-Pro-4(R)Hyp-repeated host sequence, Ac-(Gly-Pro-4(R)Hyp) 3-Gly-3(S)Hyp-4(R)Hyp-(Gly-Pro-4(R)Hyp) 4-Gly-Gly-NH 2 forms as stable a trimer (T m ؍ 49.6°C) as Ac-(Gly-Pro-4(R)Hyp) 8-Gly-Gly-NH 2 (T m ؍ 48.9°C). Given that Ac-(Gly-Pro-4(R)Hyp) 3-Gly-4(R)Hyp-Pro-(Gly-Pro-4(R)Hyp) 4-Gly-Gly-NH 2 forms a triple helix nearly as stable as the above two peptides (T m ؍ 45.0°C) and the knowledge that Ac-(Gly-4(R)Hyp-Pro) 10-NH 2 does not form a triple helix, we conclude that the host environment dominates the structure of host-guest peptides and that these peptides are not necessarily accurate predictors of triple helical stability.
Insights on the conformational stability of collagen
Natural Product Reports, 2002
This review describes work on the conformational stability of the collagen triple helix. In 1994, the structure of collagen was determined at high resolution. Since then, much work has been done on synthetic mimics of collagen that contain host-guest peptides, tethers, peptoid residues, or analogs of the prevalent 4(R)-hydroxy--proline residues. This work has revealed much about the chemical basis for collagen stability, and could spawn useful new biomaterials. The literature from 1994 to mid 2001 is reviewed, and 116 references are cited. 1 Introduction 2 Collagen mimics 2.1 Structural studies 2.2 Host-guest studies 2.3 Tethered triple-helical peptides 2.4 Peptoid residues 3 4-Substituted proline residues 3.1 Hydroxyproline residues 3.2 Aminoproline residues 3.3 Fluoroproline residues 4 Collagen as a biomaterial 5 Envoi 6 Acknowledgment 7 References Cara L. Jenkins was born in 1972 in Provo, UT. She received BS and MS degrees in chemistry from Brigham Young University. At BYU, she worked with Steven A. Fleming to develop covalently and non-covalently tethered [2 ϩ 2] photocycloaddition reactions. She is now a graduate student under the guidance of Ronald T. Raines in the chemistry department at the University of Wisconsin-Madison. As a trainee of the National Institutes of Health, Jenkins is using the methods of synthetic chemistry and biophysics to reveal the basis for the stability of collagen triple helices. She has earned both a McElvain Fellowship and the 2000 Hirschfelder Award from the chemistry department at Wisconsin. Ronald T. Raines was born in 1958 in Montclair, NJ. He received ScB degrees in chemistry and biology from the Massachusetts Institute of Technology. At MIT, he worked with Christopher T. Walsh to reveal the reaction mechanisms of pyridoxal 5Ј-phosphate-dependent enzymes. Raines was a National Institutes of Health predoctoral fellow in the chemistry department at Harvard University. There, he worked with Jeremy R. Knowles to elucidate the reaction energetics of triosephosphate isomerase. Raines was a Helen Hay Whitney postdoctoral fellow in the biochemistry and biophysics department at the University of California, San Francisco. At UCSF, he worked with William J. Rutter to clone, express, and mutate the cDNA that codes for ribonuclease A. Raines then joined the faculty at the University of Wisconsin-Madison, where he is now professor of biochemistry and chemistry. His honors include the 1998 Pfizer Award in Enzyme Chemistry from the American Chemical Society and a 2001 Guggenheim Fellowship. His research group uses techniques that span the chemistrybiology interface to reveal protein structure-function relationships in vitro and in vivo. He has published over 100 papers on this topic.