Isoform-specific Heparan Sulfate Binding within the Amino-terminal Noncollagenous Domain of Collagen α1(XI)

Warner, Lisa; Brown, Raquel J.; Yingst, Sorcha; Oxford, Julia Thom

doi:10.1074/jbc.m608551200

Cited by 29 publications

(38 citation statements)

References 48 publications

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“…A higher ‘state of charge’ (charge density) in the sulfates associated with tyrosine sulfate-rich domains of ECM proteins also enhances binding to heparin-binding protein motifs, including the OSM peptide described above (51). In a previous study we established that collagen type XI contains multiple proteoglycan binding sites that include four lysine residues K-147, K-148, K-149 and K-152 (77). Replacement of K-148, K-149 and K-152 decreased binding to heparin sulfate, whereas replacement of K-147 increased binding 5-fold (77).…”

Section: Discussionmentioning

confidence: 99%

Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis

Ryan

Martín

Mellor³

et al. 2015

Cytokine

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Oncostatin M (OSM) is an interleukin-6-like inflammatory cytokine reported to play a role in a number of pathological processes including cancer. Full-length OSM is expressed as a 26 kDa protein that can be proteolytically processed into 24 kDa and 22 kDa forms via removal of C-terminal peptides. In this study, we examined both the ability of OSM to bind to the extracellular matrix (ECM) and the activity of immobilized OSM on human breast carcinoma cells. OSM was observed to bind to ECM proteins collagen types I and XI, laminin, and fibronectin in a pH-dependent fashion, suggesting a role for electrostatic bonds that involves charged amino acids of both the ECM and OSM. The C-terminal extensions of 24 kDa and 26 kDa OSM, which contains six and thirteen basic amino acids, respectively, enhanced electrostatic binding to ECM at pH 6.5–7.5 when compared to 22 kDa OSM. The highest levels of OSM binding to ECM, though, were observed at acidic pH 5.5, where all forms of OSM bound to ECM proteins to a similar extent. This indicates additional electrostatic binding properties independent of the OSM C-terminal extensions. The reducing agent dithiothreitol also inhibited the binding of OSM to ECM suggesting a role for disulfide bonds in OSM immobilization. OSM immobilized to ECM was protected from cleavage by tumor-associated proteases and maintained activity following incubation at acidic pH for extended periods of time. Importantly, immobilized OSM remained biologically active and was able to induce and sustain the phosphorylation of STAT3 in T47D and ZR-75-1 human breast cancer cells over prolonged periods, as well as increase levels of STAT1 and STAT3 protein expression. Immobilized OSM also induced epithelial-mesenchymal transition-associated morphological changes in T47D cells. Taken together, these data indicate that OSM binds to ECM in a bioactive state that may have important implications for the development of chronic inflammation and tumor metastasis.

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Section: Discussionmentioning

confidence: 99%

Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis

Ryan

Martín

Mellor³

et al. 2015

Cytokine

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“…7), but their heparin binding has not been studied experimentally either. A very recent report (64) describes the binding of heparan sulfate to the LNS module of collagen XI ␣1 chain, the coordinating groups originating from the strand corresponding to the ␤12 of NC4. This region on the surface of the NC4 structure does contain the positive side chains of Arg 166 , Arg 177 , and Lys 184 , but they are 15-20 Å apart and do not show any chemical shift perturbation upon the heparin tetrasaccharide titration.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of the N-terminal NC4 Domain of Collagen IX, a Zinc Binding Member of the Laminin-Neurexin-Sex Hormone Binding Globulin (LNS) Domain Family

Leppänen

Tossavainen

Permi

et al. 2007

Journal of Biological Chemistry

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Collagen IX, located on the surface of collagen fibrils, is crucial for cartilage integrity and stability. The N-terminal NC4 domain of the ␣1(IX) chain is probably important in this because it interacts with various macromolecules such as proteoglycans and cartilage oligomeric matrix protein. At least 17 distinct collagen polypeptides carry an NC4-like unit near their N terminus, but this report, describing the crystal structure of NC4 at 1.8-Å resolution, represents the first atomic level structure for these domains. The structure is similar to previously characterized laminin-neurexin-sex hormone binding globulin (LNS) structures, dominated by an antiparallel ␤-sheet sandwich. In addition, a zinc ion was found in a position similar to that of the metal binding site of other LNS domains. A partial backbone NMR assignment of NC4 was obtained and utilized in NMR titration studies to investigate the zinc binding in solution state and to quantitate the affinity of metal binding. The K d of 11.5 mM suggests a regulatory rather than a structural role for zinc in solution. NMR titration with a heparin tetrasaccharide revealed the presence of a secondary binding site for heparin on NC4, showing structural and functional conservation with thrombospondin-1, but a markedly reduced affinity for the ligand. Also the overall arrangement of the N and C termini of NC4 resembles most closely the N-terminal domain of thrombospondin-1, distinguishing the two from the majority of the published LNS structures.Collagens are a family of extracellular matrix proteins comprised of at least 28 distinct types, all characterized by the presence of one or more elongated triple helical regions. This common motif is supplemented with a variety of non-helical domains to add unique properties for molecular or supramolecular assembly, for tissue-specific targeting, or for interactions with other constituents of the matrix (1, 2). An example of such a supplementary element is a module showing similarity to the N-terminal domains of thrombospondins (TSPNs) 2 (3). This domain occurs in at least 17 different collagen polypeptides, located N-terminal to the triple helix, but little is known about the detailed structures and physiological functions of these units (2).One of the TSPNs found in collagen chains is the NC4 domain of collagen IX, formed by about 245 N-terminal residues of the mature ␣1(IX) polypeptide. In cartilage tissue, collagen IX molecules are covalently bound to the heteropolymeric collagen fibrils that provide the tissue with high tensile strength to resist the swelling pressure caused by proteoglycans. The shorter arm of the triple helix of collagen IX projects away from the fibril body so that the NC4 domain can easily interact with other macromolecules. The temporal and spatial control over the presence or absence of NC4 on collagen IX via alternative splicing (4, 5) suggests that the domain has functional significance. The NC4 domain, as well as three other regions along the collagen IX triple helix, has been shown to interact...

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“…Not only does this provide a means of localising type XI collagen in the vicinity of cells through interaction with pericellular HS proteoglycans such as perlecan but this localisation helps to appropriately orientate type XI molecules on the surface of type I and II collagen fibrils to direct fibrillogenesis. (75) Although type XI collagen is a relatively minor collagen, an absolute requirement for collagen XI in skeletal growth is indicated by collagen XI deficiencies such as the hereditary chondrodystrophies found in the cho/cho mouse and in humans with Stickler syndrome. (74,76) Without the correct fibril-regulating actions of type XI collagen, articular cartilage fails to develop properly and the growth plate cartilages are disorganised and nonfunctional; thus the directional cues provided by perlecan to type XI fibrils are critical to the development of weight-and tension-bearing musculoskeletal tissues.…”

Section: Perlecan and Early Cartilage Developmentmentioning

confidence: 99%

Perlecan, the “jack of all trades” proteoglycan of cartilaginous weight‐bearing connective tissues

et al. 2008

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Perlecan is a ubiquitous proteoglycan of basement membrane and vascularized tissues but is also present in articular cartilage, meniscus and intervertebral disc, which are devoid of basement membrane and predominantly avascular. It is a prominent pericellular proteoglycan in the transitory matrix of the cartilaginous rudiments that develop into components of diarthrodial joints and the axial skeleton, and it forms intricate perichondrial vessel networks that define the presumptive articulating surfaces of developing joints and line the cartilage canals in cartilaginous rudiments. Such vessels have roles in the nutrition of the expanding cell numbers in the developing joint. Perlecan sequesters a number of growth factors pericellularly (FGFs, PDGF, VEGF and CTGF) and through these promotes cell signalling, cell proliferation and differentiation. Perlecan also interacts with a diverse range of extracellular matrix proteins, stabilising and organising the ECM, and promoting collagen fibrillogenesis. Perlecan is a prominent pericellular component of mesenchymal cells from their earliest developmental stages through to maturation, forming cell-cell and cell-ECM interconnections that are suggestive of a role in mechanosensory processes important to tissue homeostasis.

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Isoform-specific Heparan Sulfate Binding within the Amino-terminal Noncollagenous Domain of Collagen α1(XI)

Cited by 29 publications

References 48 publications

Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis

Oncostatin M binds to extracellular matrix in a bioactive conformation: Implications for inflammation and metastasis

Crystal Structure of the N-terminal NC4 Domain of Collagen IX, a Zinc Binding Member of the Laminin-Neurexin-Sex Hormone Binding Globulin (LNS) Domain Family

Perlecan, the “jack of all trades” proteoglycan of cartilaginous weight‐bearing connective tissues

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