A role for disulphide bridges in the protein core in the interaction of proteodermatan sulphate and collagen

Scott, Paul; Winterbottom, Neil; Dodd, Carole M.; Edwards, E.A.; Pearson, C. H.

doi:10.1016/s0006-291x(86)80431-4

Cited by 79 publications

(36 citation statements)

References 17 publications

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“…Similarly, both the spectral behavior and apo(a) binding were restored when our decorin preparation was first heated to 65°C and then cooled to 25°C. This conformational and functional reversibility of decorin is in keeping with the results by Scott et al (45) and Renugopalakrishnan et al (46) and with the recent studies by this laboratory using plasminogen instead of apo(a) in the binding system. 2 However, this notion of reversibility appears to be at variance with the results of the studies of Ramamurthy et al (44) who failed to renature their recombinant decorin which was purified from the cell medium in the presence of 4 M GdnHCl and 0.5% Triton X-100.…”

Section: Discussionsupporting

confidence: 91%

“…Previous investigations on either recombinant decorin purified from cell medium by nickel column chromatography (44) or decorin extracted from tissues in the presence of the chaotropic agent, GdnHCl, subsequently removed by a combination of dialysis and lyophilization procedures (45), have shown that conservation of the native structure is essential for the biological function of this proteoglycan. Our decorin preparations exhibited CD spectra comparable to those reported for decorin (44 -46) and GD decorin (45,46). Moreover, according to our results, decorin first denatured in the presence of 4 M GdnHCl and renatured by extensive dialysis is able to resume its native conformation and ability to bind to apo(a).…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

Klezovitch¹,

Edelstein²,

Zhu³

et al. 1998

Journal of Biological Chemistry

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Although it is known that lipoprotein(a) (Lp(a)) binds to proteoglycans, the mechanism for this binding has not been fully elucidated. In order to shed light on this subject, we examined the interactions of decorin, a proteoglycan with a well defined protein core and a single glycosaminoglycan (GAG) chain, with Lp(a) and derivatives, namely Lp(a) deprived of apo(a), or Lp(a؊), free apo(a), and the two main proteolytic fragments, F1 and F2. By circular dichroism criteria, the decorin preparations used had the same secondary structure as that previously reported for native decorin. Authentic low density lipoprotein from the same human donor was used as a control. In a solid phase system, Lp(a؊)and low density lipoprotein bound to decorin in a comparable manner. This binding required Ca 2؉ /Mg 2؉ ions, was lysine-mediated, and was markedly decreased in the presence of GAG-depleted decorin, suggesting the ionic nature of the interaction likely involving apoB100 and the GAG component of decorin. Free apo(a) also bound to decorin; however, the binding was neither cation-dependent nor lysine-mediated, unaffected by sialic acid depletion of apo(a), and markedly decreased when either reduced and alkylated apo(a) or reduced and alkylated decorin was used in the assay. Of note, the binding of apo(a) was unaffected when it was incubated with a spectrally native decorin that had been renatured from either 4 M guanidine hydrochloride by extensive dialysis or cooled from 65 to 25°C. On the other hand, the binding significantly increased when decorin was depleted of GAGs, which by themselves had no affinity for apo(a). The binding of apo(a) to the decorin protein core was also elicited by the C-terminal domain of apo(a), and it was favored by high NaCl concentrations, 1 to 2 M. No binding was exhibited by the N-terminal domain accounting for the lack of effect of apo(a) size polymorphism on the binding. In the case of whole Lp(a), the binding to immobilized decorin was mostly GAGdependent and ionic in nature. A minor contribution by apo(a) was detected when GAG-depleted decorin was used in the assay. Our results indicate that the binding of Lp(a) to decorin involves interactions both electrostatic (apoB100-GAG) and hydrophobic (apo(a)-decorin protein core), and that the binding of apo(a) requires decorin protein core to be in its native state.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

Klezovitch¹,

Edelstein²,

Zhu³

et al. 1998

Journal of Biological Chemistry

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“…Moreover, the coordinated expression of decorin together with associated collagens is responsible for correct assembly and behavior of the ECM (48). Decorin is able to retard the rate and degree of collagen fibrillogenesis in vitro (49), and the glycosaminoglycan chain of decorin extends laterally from adjacent collagen fibrils, thereby maintaining interfibrillar spacing (50,51). Posttranslational modifications (chondroitin-or dermatan-sulfate side chains) can influence the biological activities of decorin (6,15,24), but whether increased concentration of decorin has an impact on ECM organization is not yet clear.…”

Section: Discussionmentioning

confidence: 99%

Overexpressed Decorin in Pancreatic Cancer

Köninger

Giese

Mola

et al. 2004

Clinical Cancer Research

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Purpose: The aim of this study was to investigate the expression and significance of decorin in pancreatic cancer.Experimental Results: Pancreatic cancer was characterized by striking overexpression of decorin mRNA in tumor tissues (9-fold by real-time quantitative PCR; 44 patients versus 18 healthy donors; P < 0.01). Strong decorin immunostaining was observed in the extracellular matrix of pancreatic cancer tissue, whereas tumor cells were devoid of decorin. Double staining for anti-smooth muscle actin and decorin and reverse transcription-PCR analysis of primary cultures revealed pancreatic stellate cells as the putative source of decorin. Human recombinant decorin was able to suppress growth of pancreatic cancer cells in vitro through p21-mediated G 1 -S block of the cell cycle. However, in contrast to the previously described chemotherapy-potentiating capacity of decorin, this proteoglycan attenuated the cytostatic action of carboplatin and gemcitabine toward pancreatic cancer cells.Conclusions: Decorin might exert an antiproliferative effect toward pancreatic cancer cells, thus playing a role in a host stromal reaction aimed at sequestering and inhibiting growing malignant cells. However, in clinical settings, the importance of collagen-associated decorin as a moderate antitumor modality would be undermined by its ability to attenuate the efficiency of chemotherapeutics. Considering the general failure of adjuvant therapies in pancreatic cancer, the role of decorin in this process warrants further investigation.

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“…Two different decorin samples have been used in this study: a recombinant decorin (DcnR), expressed in HEK 293A cells and purified without chaotropic agents, and a tissue-derived decorin (DcnT), extracted from calfskin and refolded from solutions containing urea. Both forms have been shown to be biologically active as they interact with collagen, inhibit collagen fibrillogenesis, and inhibit fibroblast proliferation (9,25) (Fig. 5, which is published as supporting information on the PNAS web site).…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan

Scott

McEwan

Dodd

et al. 2004

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

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192

228

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Decorin is a ubiquitous extracellular matrix proteoglycan with a variety of important biological functions that are mediated by its interactions with extracellular matrix proteins, cytokines, and cell surface receptors. Decorin is the prototype of the family of small leucine-rich repeat proteoglycans and proteins (SLRPs), characterized by a protein core composed of leucine-rich repeats (LRRs), flanked by two cysteine-rich regions. We report here the crystal structure of the dimeric protein core of decorin, the best characterized member of the SLRP family. Each monomer adopts the curved solenoid fold characteristic of LRR domains, with a parallel ␤-sheet on the inside interwoven with loops containing short segments of ␤-strands, 310 helices, and polyproline II helices on the outside. Two main features are unique to this structure. First, decorin dimerizes through the concave surfaces of the LRR domains, which have been implicated previously in protein-ligand interactions. The amount of surface buried in this dimer rivals the buried surfaces of some of the highest-affinity macromolecular complexes reported to date. Second, the C-terminal region adopts an unusual capping motif that involves a laterally extended LRR and a disulfide bond. This motif seems to be unique to SLRPs and has not been observed in any other LRR protein structure to date. Possible implications of these features for decorin ligand binding and SLRP function are discussed.

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A role for disulphide bridges in the protein core in the interaction of proteodermatan sulphate and collagen

Cited by 79 publications

References 17 publications

Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

Apolipoprotein(a) Binds via Its C-terminal Domain to the Protein Core of the Proteoglycan Decorin

Overexpressed Decorin in Pancreatic Cancer

Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan

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