Characterization of the N-terminal region of decorin, a small leucine-rich proteoglycan /
A dermatan sulfate/chondroitin sulfate small leucine-rich proteoglycan, decorin associates with and regulates the assembly of collagen fibrils in mammalian extracellular matrix. Earlier studies of decorin structure/function revealed that the N-terminal region of the core protein forms a complex wit...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
2004.
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| Subjects: | |
| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=766020671&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | A dermatan sulfate/chondroitin sulfate small leucine-rich proteoglycan, decorin associates with and regulates the assembly of collagen fibrils in mammalian extracellular matrix. Earlier studies of decorin structure/function revealed that the N-terminal region of the core protein forms a complex with 2 Zn²⁺ ions, regulating homotypical and heterotypical interactions. This dissertation reports mechanistic details surrounding the function of the N-terminal region as well as the putative physiological impact(s) of decorin on blood coagulation. Decorin binds to fibrinogen in a Zn²⁺-dependent interaction during solid and solution phase experiments. An interface encompasses the N-terminal region of decorin and the D region of fibrinogen. According to gel filtration chromatography, a peptide mimicking the N-terminal region forms an oligomer in the presence of Zn²⁺ ions that dissociates under reducing, metal-chelating conditions. Mutational analysis of truncated and alanyl-substituted variants of this region indicates that residues D42, C49, C53, H56, C62, D64 and D68 participate in the binding of 2 Zn²⁺ ions. Alternatively, D40 is required for effective fibrinogen-recognition. Decorin proteoglycan from mammalian cells or the decorin peptide slows the progress of clotting in a Zn²⁺ and decorin concentration-dependent fashion in vitro. These observations indicate that the N-terminal region of decorin core protein intrinsically exhibits anticoagulant activity attributable to fibrinogen-binding. A greater anticoagulant potency characterizing decorin proteoglycan suggests the steric and/or electrostatic perturbation of fibrin assembly. Decorin proteoglycan extrinsically inhibits thrombin by activating heparin cofactor II, corroborating previous reports. However, an intrinsic antithrombin activity of decorin proteoglycan was not detected. Collectively, while only dermatan sulfate decorin glycoforms can inhibit thrombin via heparin cofactor II, all molecular forms of decorin comprising the N-terminal, Zn²⁺-binding region harbor a potential anticoagulant activity stemming from interaction with fibrinogen. These results also suggest that decorin proteoglycan may influence the architecture of provisional fibrin(ogen) matrix, perhaps influencing wound repair at the onset. |
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| Item Description: | Vita. "Major Subject: Biochemistry". |
| Physical Description: | xii, 160 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 141-159). |