The Decorin Sequence SYIRIADTNIT Binds Collagen Type I

Journal of Biological Chemistry

Oldberg

2009

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Lumican and fibromodulin compete for collagen type I binding in vitro, and fibromodulin-deficient mice have 4-fold more lumican in tendons. These observations indicate that homologous sequences in lumican and fibromodulin bind to collagen type I. Here, we demonstrate that lumican binding to collagen type I is mediated mainly by Asp-213 in leucine-rich repeat (LRR) 7. The mutation D213N in lumican impairs interaction with collagen, and the lumican fragment spanning LRRs 5-7 is an efficient inhibitor of collagen binding. Also, the lumican LRR 7 sequence-based synthetic peptide CYLDNNKC inhibits the binding to collagen. Homologous collagen-binding site in fibromodulin, located in LRRs 5-7, inhibits the binding of lumican to collagen, and the mutation E251Q in this fibromodulin fragment does not inhibit the lumican-collagen binding. Lumican, but not the D213N mutation, lowers the melting point and affects the packing of collagen fibrils.

Section: Discussionmentioning

confidence: 99%

Homologous Sequence in Lumican and Fibromodulin Leucine-rich Repeat 5-7 Competes for Collagen Binding

Journal of Biological Chemistry

Oldberg

2009

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“…We have recently identified Asp-210 of decorin as a critical collagen-binding residue (37). In addition, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Collagen Fibrillogenesis Assay-The assays were performed as described previously (37). Pepsin-extracted acid-solubilized collagen (Vitrogen) was neutralized and diluted (167 pM) in 150 mM NaCl, 20 mM HEPES, pH 7.4, with fibromodulin or mutated fibromodulins at 4°C.…”

Section: Expression Of Gst-tagged Fibromodulin Fragments Inmentioning

confidence: 99%

Fibromodulin Binds Collagen Type I via Glu-353 and Lys-355 in Leucine-rich Repeat 11

Journal of Biological Chemistry

Oldberg

2007

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Fibromodulin belongs to the small leucine-rich repeat proteoglycan family, interacts with collagen type I, and controls collagen fibrillogenesis and assembly. Here, we show that a major fibromodulin-binding site for collagen type I is located in leucine-rich repeat 11 in the C terminus of the leucine-rich repeat domain. We identified Glu-353 and Lys-355 in repeat 11 as essential for binding, and the synthetic peptide RLDGNEIKR, including Glu-353 and Lys-355, inhibits the binding of fibromodulin to collagen in vitro. Fibromodulin and lumican compete for the same binding region on collagen, and fibromodulin can inhibit the binding of lumican to collagen type I. However, the peptide RLDGNEIKR does not inhibit the binding of lumican to collagen, suggesting separate but closely situated fibromodulin-and lumican-binding sites in collagen. The collagenbinding Glu-353 and Lys-355 residues in fibromodulin are exposed on the exterior of the ␤-sheet-loop structure of the leucine-rich repeat, which resembles the location of interacting residues in other leucine-rich repeat proteins, e.g. decorin.Fibromodulin is an extracellular matrix proteoglycan expressed in dense regular connective tissues, including ligaments, cartilage, and tendons (1). Fibromodulin belongs to the small leucine-rich repeat proteoglycan family (SLRPs) 2 (2, 3), which also includes e.g. biglycan (4), decorin (5), and lumican (6). These SLRPs are involved in the regulation of collagen fibril formation and matrix assembly, as demonstrated in SLRP-deficient mice (7). Decorin-deficient mice have fragile skin (8), fibromodulin deficiency leads to weak tendons and ligaments, causing osteoarthritis (9, 10), and lumican-deficient mice have opaque corneas (11). All these genotypes mediate an abnormal development of collagen matrices.Fibromodulin and lumican are differentially expressed in developing tendons and possibly act in a coherent manner to regulate collagen matrix assembly (12), as they bind to the same region of collagen, different from the decorin-binding site (13). Fibromodulin binds preferentially in the gap region of assembled collagen fibrils (14) and affects the growth of collagen type I fibrils in vitro, as it binds to collagen monomers and delays their accretion to the growing fibrils (15). Collagen fibrils in tendon of fibromodulin-deficient mice are irregularly shaped with a higher proportion of thin fibrils, in contrast to fibrils formed in wild type mice (9). In addition, fibromodulin also binds collagen type XII (16) and transforming growth factor-␤ (17).It has also been proposed that fibromodulin and other collagen-binding SLRPs have a function in protecting collagen from collagenase degradation in connective tissues (18). Genomic analysis suggests a role for fibromodulin in metastasis (19), and the proteoglycan is also up-regulated in chronic lymphoid leukemia (20). Fibromodulin is one of just 14 genes progressively changed in expression with age and in progeria (21,22). Fibromodulin is also implicated in pathways of inflammatory response ...

“…Decorin is involved in collagen type I fibril formation and matrix assembly in a wide range of connective tissues and binds near the C terminus of collagen monomers, delaying their accretion to the growing fibrils. We have identified an SYIRIADTNIT sequence in decorin as essential for binding to collagen (16). The role of the decorin CS/DS chain in vivo has not been explored, although in vitro studies suggest that IdoA promotes the binding of CS/DS to collagen (31) and is required for self-association of CS/DS chains (6,10,22).…”

mentioning

confidence: 99%

Dermatan Sulfate Epimerase 1-Deficient Mice Have Reduced Content and Changed Distribution of Iduronic Acids in Dermatan Sulfate and an Altered Collagen Structure in Skin

Maccarana¹,

Molecular and Cellular Biology

Kongsgaard

et al. 2009

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128

Dermatan sulfate epimerase 1 (DS-epi1) and DS-epi2 convert glucuronic acid to iduronic acid in chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the chondroitin/dermatan polysaccharide chains. The numbers of long blocks of adjacent iduronic acids are greatly decreased in skin decorin and biglycan chondroitin/dermatan sulfate, along with a parallel decrease in iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican-derived chains. DS-epi1-deficient mice are smaller than their wild-type littermates but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the chondroitin/dermatan sulfate in many proteoglycans, and the consequences for skin collagen structure were initially analyzed. We found that the skin collagen architecture was altered, and electron microscopy showed that the DS-epi1-null fibrils have a larger diameter than the wild-type fibrils. The altered chondroitin/dermatan sulfate chains carried by decorin in skin are likely to affect collagen fibril formation and reduce the tensile strength of DS-epi1-null skin.