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Proteoglycan Structure
Published by Anonymous on 2007/9/30 (3065 reads)
1: Vasc Health Risk Manag. 2007;3(1):117-24.


Vascular wall proteoglycan synthesis and structure as a target for the prevention of atherosclerosis.

Little PJ, Ballinger ML, Osman N.

Cell Biology of Diabetes Laboratory, Baker Heart Research Institute, Melbourne, Australia. peter.little@baker.edu.au

Atherosclerosis is the underlying pathology of most cardiovascular disease and it represents the major cause of premature death in modern societies. Current therapies target risk factors being hypertension, hypercholesterolemia, hypertriglyceridemia and hyperglycemia when diabetes is present however the maximum efficacy of these strategies is often 30% or less. Areas of vascular biology that may lead to the development of a complementary vascular wall directed therapy are: inflammation, oxidation, endothelial dysfunction, diabetes-specific factors--hyperglycemia and advanced glycation endproducts and lipid retention by vascular matrix specifically proteoglycans. The major structural features of proteoglycans that determine low-density lipoprotein (LDL) binding are the length and sulfation pattern on the glycosaminoglycan (GAG) chains. Emerging data discussed in this review indicates that these structural properties are subject to considerable regulation by vasoactive substances possibly using novel signaling pathways. For example, GAG elongation stimulated by platelet-derived growth factor is not blocked by the receptor tyrosine kinase antagonist, genistein suggesting that there may be a previously unknown signaling pathway involved in this response. Thus, modifying proteoglycan synthesis and structure may represent a prime target to prevent LDL binding and entrapment in the vessel wall and thus prevent the development and progression of atherosclerosis.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 17583182 [PubMed - indexed for MEDLINE]

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2: Clin Calcium. 2004 Jul;14(7):9-14.


[Cartilage proteoglycan aggregate: structure and function]

[Article in Japanese]

Watanabe H.

Institute for Molecular Science of Medicine, Aichi Medical University.

The proteoglycan aggregate is the major structural component of the extracellular matrix of the cartilage, composed of aggrecan, hyaluronan (HA) and link protein (LP). The aggregates provide cartilage with unique gel-like property and resistance to deformation through water absorption. Natural knockout mice of aggrecan, termed cartilage matrix deficiency, and LP-null mice exhibit decreased levels of aggrecan depositon in cartilage and correspond well with their phenotypes such as dwarfism and spinal misalignment, demonstrating in vivo roles of the aggregate in cartilage development and homeostasis. Our recent studies demonstrate that versican/PG-M, another member of aggrecan family with a similar domain structure, binds both HA and LP, forming an aggregate. Further functional analyses of domains and subdomains showed distinct interaction of versican/PG-M with LP from aggrecan, suggesting that the versican/PG-M aggregate may have different function in cartilage.

Publication Types:
English Abstract
Review

PMID: 15577070 [PubMed - indexed for MEDLINE]

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3: Glycoconj J. 2004;21(1-2):53-7.


Neuroglycan C, a brain-specific part-time proteoglycan, with a particular multidomain structure.

Oohira A, Shuo T, Tokita Y, Nakanishi K, Aono S.

Department of Perinatology and Neuroglycoscience, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi 480-0392, Japan. oohira@inst-hsc.jp

Neuroglycan C (NGC) is a transmembrane-type of chondroitin sulfate proteoglycan that is exclusively expressed in the central nervous system. NGC gene expression is developmentally regulated, and is altered by addiction to psychostimulants and by nerve lesion. Its core protein has a particular multidomain structure differing from those of other known proteoglycans, and this protein is modified post-translationally in various ways such as phosphorylation and glycosylation. NGC is a novel part-time proteoglycan that changes its structure from a proteoglycan form to a non-proteoglycan form without chondroitin sulfate chains during the development of the cerebellum and retina. Results obtained from immunohistological, cell biological and biochemical experiments suggest that NGC is involved in neuronal circuit formation in the central nervous system. To verify the proposed functions of NGC in the brain, production and phenotype-analyses are being performed in mice with various NGC gene mutations causing the expression or glycosylation of NGC to be altered.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15467399 [PubMed - indexed for MEDLINE]

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4: Biochim Biophys Acta. 2002 Dec 19;1573(3):312-8.


Heparan sulfate fine structure and specificity of proteoglycan functions.

Nakato H, Kimata K.

Department of Molecular and Cellular Biology, and Arizona Cancer Center, University of Arizona, Tucson 85724, USA. hnakato@azcc.arizona.edu

Heparan sulfate chains have markedly heterogeneous structures in which distinct patterns of sulfation determine the binding specificity for ligand proteins. These "fine structures" of heparan sulfate are mainly produced by the regulated introduction of sulfate groups at the N-, 2-O-, 6-O-, and 3-O-positions of the sugar chain. Recent biochemical, histochemical, and genetic studies have demonstrated that different fine structures mediate distinct molecular recognition events to regulate a variety of cellular functions. In this review, we focus on the molecular basis of growth factor control by the sulfation status of heparan sulfate.

Publication Types:
Review

PMID: 12417413 [PubMed - indexed for MEDLINE]

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5: Pathol Biol (Paris). 2001 May;49(4):364-75.


[Structure and regulation of articular cartilage proteoglycan expression]

[Article in French]

Rédini F.

Laboratoire de biochimie du tissu conjonctif, faculté de médecine, niveau 3, 14032 Caen, France.

Beyond aggrecan, the major proteoglycan present in articular cartilage that confers resistance to compressive load and viscoelasticity to the tissue, other proteoglycan families have been described in cartilage. Among them, decorin, biglycan and fibromodulin which belong to the small leucine-rich proteoglycans family bind to matrix components, specially to collagen fibrils and thus regulate fibrillogenesis in cartilage and matrix integrity. These small proteoglycans can also interact with TGF-beta and modulate its bioavailability and stability. The third family is composed by cell surface proteoglycans as syndecans, glypican-1 and betaglycan. These molecules interact with various components of cell environment (growth factors, proteases, matrix components, etc.) and mediate numerous cell functions. Some modifications of one of these proteoglycan expression occur during degenerative pathologies and may lead to alteration of the functional properties of the tissue as well as variations in growth factor bioavailability. These factors are involved in the attempt of cartilage repair initiated by chondrocytes in the early stages of osteoarthritis.

Publication Types:
English Abstract
Review

PMID: 11428173 [PubMed - indexed for MEDLINE]

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6: J Biochem (Tokyo). 1998 Oct;124(4):687-93.


Roles of aggrecan, a large chondroitin sulfate proteoglycan, in cartilage structure and function.

Watanabe H, Yamada Y, Kimata K.

Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental Research, National Institutes of Health, Bethesda MD 20892, USA. watanabe@yoda.nidr.nih.gov

Aggrecan, a large aggregating proteoglycan, is one of the major structural components of cartilage. Its core protein contains three glubular domains and two glycosaminoglycan-attachment domains. These domains play various roles to maintain cartilage structure and function. An N-terminal globular domain binds hyaluronan and link protein to form huge aggregates. The chondroitin sulfate (CS) chains attach to the CS domain and provide a hydrated, viscous gel that absorbs compressive load. Two autosomal recessive chondrodysplasias, cartilage matrix deficiency (cmd) in mice and nanomelia in chicken are both caused by aggrecan gene mutations. Cmd homozygotes die shortly after birth, while the heterozygotes are born normal. However, cmd heterozygotes develop late onset of spinal disorder, which suggests aggrecan as a candidate gene predisposing individuals to spinal problems. Nanomelia is a useful model to elucidate intracellular trafficking of proteoglycans. Further studies on aggrecan will lead to prophylaxis and treatment of joint destructive diseases such as osteoarthrosis and to elucidation of cartilage development, which is essential for skeletal formation.

Publication Types:
Review

PMID: 9756610 [PubMed - indexed for MEDLINE]

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7: Perspect Dev Neurobiol. 1996;3(4):331-46.


N-syndecan: structure and function of a transmembrane heparan sulfate proteoglycan.

Carey DJ.

Sigfried and Janet Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.

N-syndecan is a member of the syndecan family of transmembrane heparan sulfate proteoglycans that was cloned initially from neonatal rat Schwann cells and is the principal syndecan expressed during early postnatal development in the central and peripheral nervous systems. Purified N-syndecan binds in vitro with high affinity to several extracellular regulatory ligands, including basic fibroblast growth factor, the secreted adhesive protein heparin binding growth-associated molecule, and a novel collagen-like protein secreted by Schwann cells. These extracellular ligands utilize the heparan sulfate chains of N-syndecan for binding. Based on the striking amino acid sequence homology of the cytoplasmic domain of N-syndecan to syndecan-1, it is proposed that N-syndecan associates with the actin-based cytoskeleton. N-syndecan core proteins self associate by means of an unusual dimerization motif comprised of the transmembrane domain and a short flanking sequence in the ectodomain. Similar to other single transmembrane domain receptor proteins, it is suggested that ligand-regulated dimerization of N-syndecan represents a mechanism for regulating downstream signaling activities. In rat brain tissue a significant fraction of the N-syndecan molecules are present in a soluble form, presumably as a result of proteolytic membrane shedding. A model is presented for morphoregulatory activity of N-syndecan in which extracellular ligand-induced clustering of N-syndecan molecules on the cell surface promotes cytoskeletal association and reorganization. Membrane shedding separates the functional domains of the proteoglycan and terminates this activity.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9117264 [PubMed - indexed for MEDLINE]

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8: Rinsho Byori. 1995 Oct;43(10):979-87.


[Structure and function of extracellular matrix with special references to proteoglycan]

[Article in Japanese]

Takeuchi J.

Department of Laboratory Medicine, Nagoya University School of Medicine.

To clarify the physiological significance of extracellular matrix components, biochemical and histochemical characterization of glycosaminoglycan and proteoglycan was performed. The glycosaminoglycan, chondroitin sulfate, was favorable to the growth of Ehrlich ascite tumor cells inoculated into the subcutaneous space of the mouse's back. The glycosaminoglycan content and its synthesis by gastric carcinoma tissue were compared with those of non-neoplastic mucosa, after incubation of tissue segments in medium containing 35SO4. The rate of glycosaminoglycan synthesis by medullary carcinoma tissue was much higher than that by the non-neoplastic mucosa, although no significant difference was found in the amount of glycosaminoglycan between them. Using human gastric carcinoma cell lines, the interaction of fibroblasts (cell line WI-38) with carcinoma cells was studied in vitro. In well-differentiated adenocarcinoma, the amount of glycosaminoglycan secreted into the interface between carcinoma cells and fibroblasts was much larger (about 20-fold) than that into the interface between the carcinoma cells and the bare culture dish. However, in poorly differentiated adenocarcinoma cells, glycosaminoglycan secretion was not affected by the presence of fibroblasts. The effects of the extracellular matrix produced by carcinoma cells on the attachment and growth of fibroblasts were also examined in vitro. The attachment-promoting and growth-promoting activities of the matrix substance produced by poorly differentiated carcinoma was about 10 times greater than that caused by the well-differentiated adenocarcinoma cell matrix substance. Proteoglycan and glycosaminoglycan were identified in malignant and benign non-epithelial tumors. More proteoglycans containing mainly chondroitin sulfate could be detected in malignant tumors than in benign tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication Types:
English Abstract
Review

PMID: 8531395 [PubMed - indexed for MEDLINE]

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9: Eur J Clin Chem Clin Biochem. 1994 Apr;32(4):249-57.


The structure, function and turnover of aggrecan, the large aggregating proteoglycan from cartilage.

Hardingham TE, Fosang AJ, Dudhia J.

Kennedy Institute of Rheumatology, Hammersmith, London, UK.

Aggrecan, the large aggregating proteoglycan from cartilage contains chondroitin sulphate and keratan sulphate attached to a multidomain protein core. It aggregates by binding to hyaluronan and this is further stabilised by a separate globular link protein. There are two structurally related N-terminal globular domains, G1 and G2, of which only G1 and not G2 is involved in aggregation. The interglobular domain joining G1 and G2 contains proteinase sensitive sequences which appear to be the key site for cleavage during aggrecan turnover. Much of the keratan sulphate and all of the chondroitin sulphate is attached to the long extended glycosaminoglycan attachment region. The function of the C-terminal G3 domain is unknown. It contains a mammalian type C lectin and complement regulatory protein motifs. These may have interactive properties that contribute to matrix organisation. There is also an alternatively spliced form with an epidermal growth factor-like motif. The carbohydrate composition of aggrecan varies with cartilage source, development and age and is heterogeneous in each sample. There is evidence of a close control of chondroitin sulphate synthesis that determines chain length and disaccharide composition and which change during development and in pathology. Monoclonal antibodies that recognise specific sequences within chondroitin sulphate chains enable some of these changes in fine structure to be detected. Progressive digestion of chains with chondroitinase AC II has provided evidence of a pattern of sulphation, with 6-sulphated disaccharides more abundant towards the protein core, although the disaccharide next to the linkage region is predominantly non-sulphated.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8038265 [PubMed - indexed for MEDLINE]

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10: Behring Inst Mitt. 1993 Dec;(93):214-23.


C1q inhibitor (chondroitin-4-sulfate proteoglycan): structure and function.

Ghebrehiwet B, Galanakis DK.

Department of Medicine, State University of New York 11794-8161.

The serum C1q inhibitor (C1q INH) is a chondroitin 4-sulfate proteoglycan which is composed of several polyanionic components ranging in size from 21-750 kDa. Although the activity of C1q INH has been described in terms of its ability to precipitate C1q and inhibit its hemolytic activity, not much is known about either the mechanisms of its action or its role in health and disease. This report provides evidence that a 30 kDa core protein component of the proteoglycan macromolecule contains most of the C1q inhibitory activity. This inhibitory activity occurs as a result of C1q INH binding to the C1q "heads" (gC1q) as well as to the collagen "tail" (cC1q). What may be more significant in terms of perpetuation of inflammatory processes is the ability of C1q INH to moderately activate the classical pathway leading to C2 and C4 consumption. The binding of C1q INH to C1q is enhanced at low ionic strength, but significant binding does occur under physiologic conditions which makes it likely for the inhibitor to participate in inflammatory processes especially in microenvironments of high inhibitor concentration. Such elevated concentration does occur in patients with active rheumatoid arthritis and systemic lupus erythematosus either as a result of unregulated proteoglycan synthesis or disturbances in connective tissue metabolism. Another important function of serum C1q INH is its ability to prolong the clotting time of plasma and fibrinogen solutions containing or lacking CaCl2. This potent anticoagulant activity is again displayed by the 30 kDa putative protein core which specifically binds to both the E and D domains of fibrinogen. However, the epitope(s) on the 30 kDa which binds to C1q appears to be distinct from that which binds to fibrinogen. The known presence of proteoglycans on the basement membranes and other sites may explain at least in part the presence of fibrinogen in atheromatous lesions. Furthermore, by binding to fibrinogen, soluble C1q INH-and C1q-C1q INH complexes may limit fibrin gelation in inflammatory and tissue repair microenvironments.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 8172570 [PubMed - indexed for MEDLINE]

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11: Curr Opin Cell Biol. 1991 Oct;3(5):805-16.


Genetic analysis of proteoglycan structure, function and metabolism.

Esko JD.

University of Alabama, Birmingham.

Significant progress has been made in understanding the structure, function, and metabolism of proteoglycans. Many of the advances derive from the application of recombinant DNA methodology to their core proteins and from the characterization of animal cell mutants altered in glycosaminoglycan synthesis.

Publication Types:
Review

PMID: 1931081 [PubMed - indexed for MEDLINE]

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12: Ann Biol Clin (Paris). 1991;49(4):199-207.


[Thrombomodulin: a new proteoglycan. Structure-function relation]

[Article in French]

Bourin MC.

Laboratoire de Biotechnologie des Cellules Eucaryotes, Université Paris Val-de-Marne, Créteil.

The endothelial cell surface receptor thrombomodulin (TM) displays various anticoagulant functions: it acts as a cofactor for the activation of protein C (PC) by thrombin, prevents the activation of fibrinogen, platelets and Factor V by thrombin. TM was also shown to accelerate the inhibition of thrombin by its physiological inhibitor antithrombin III (ATIII). The studies performed on rabbit lung TM were undertaken in order to provide better understanding, along with the identification and the characterization of functional domains, to the mechanism of action of TM. On the basis of the physical and chemical properties of TM, which were compatible with those of a proteoglycan, the presence of a sulfated polysaccharide chain covalently bound to TM, constituting an acidic domain independent of the protein C activation cofactor site, was suggested. Further enzymatic and chemical characterization showed that rabbit TM was in fact a chondroitin sulfate proteoglycan. Monoclonal antibodies raised against rabbit TM and proteins known for their ability to neutralize the activity of heparin, as well as TM submitted to chondroitinase digestion were used in order to identify the role of the different structural domains of TM. Binding of thrombin to TM at a primary site on the protein part is a prerequisite for all the biological activities of TM. However, while this binding is sufficient for TM to promote the activation of PC by thrombin, the inhibition by TM of thrombin-induced fibrinogen clotting and factor V activation requires the interaction of thrombin at a secondary site with the polysaccharide chain of TM. This interaction with the polysaccharide chain (which carries a highly sulfated trisaccharide at the non-reducing terminus) leads to the inhibition of the procoagulant functions of TM-bound thrombin towards fibrinogen and factor V as well as an increased reactivity of the enzyme with ATIII. These results were rationalized in the functional model proposed for the rabbit TM-proteoglycan. An original aspect of the TM-proteoglycan resides in the fact that the chondroitin sulfate side chain brings new anticoagulant activities, in addition to the PC activation cofactor activity, to the molecule. TM is a new type of proteoglycan with important regulatory function in hemostasis, which anticoagulant properties depend on both the protein core and the polysaccharide chain.

Publication Types:
English Abstract
Review

PMID: 1656816 [PubMed - indexed for MEDLINE]

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13: Biochem Soc Trans. 1990 Oct;18(5):799-802.


Proteoglycan structure and metabolism during maturation and ageing of human articular cartilage.

Bayliss MT.

Division of Biochemistry, Kennedy Institute of Rheumatology, Hammersmith, London, U.K.

Publication Types:
Review

PMID: 2083680 [PubMed - indexed for MEDLINE]

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14: Agents Actions Suppl. 1986;18:19-29.


Changes in cartilage proteoglycan structure during ageing: origin and effects--a review.

Roughley PJ.

Publication Types:
Review

PMID: 3524147 [PubMed - indexed for MEDLINE]

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15: Ann N Y Acad Sci. 1985;454:52-68.


Proteoglycan structure and function as related to atherosclerosis.

Wagner WD.

Publication Types:
In Vitro
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 3935030 [PubMed - indexed for MEDLINE]

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16: Clin Orthop Relat Res. 1983 Jan-Feb;(172):207-32.


Proteoglycan structure in calcifying cartilage.

Buckwalter JA.

Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 6337000 [PubMed - indexed for MEDLINE]
 

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