title: Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.
abstract: The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin. Its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase (a major collagen cross-linking enzyme) and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Together, the data suggest a fibromodulin-modulated collagen cross-linking mechanism where fibromodulin binds to a specific part of the collagen domain and also forms a complex with lysyl oxidase, targeting the enzyme toward specific cross-linking sites.
authors.affiliation: From the Department of Laboratory Medical Sciences, Lund University, Medicon Village 406-3, 22363 Lund, Sweden and sebastian.kalamajski@med.lu.se.
authors.forename: Sebastian
authors.identifier: http://orcid.org/0000-0002-6600-9302
authors.initials: S
authors.lastname: Kalamajski
authors.affiliation: the Department of Biochemistry, Downing Site, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bihan
authors.affiliation: the Department of Biochemistry, Downing Site, University of Cambridge, Cambridge CB2 1QW, United Kingdom.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Bonna
authors.affiliation: From the Department of Laboratory Medical Sciences, Lund University, Medicon Village 406-3, 22363 Lund, Sweden and.
authors.forename: Kristofer
authors.initials: K
authors.lastname: Rubin
authors.affiliation: the Department of Biochemistry, Downing Site, University of Cambridge, Cambridge CB2 1QW, United Kingdom rwf10@cam.ac.uk.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003094:Collagen / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D000071235:Fibromodulin; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D060066:Protein Interaction Maps; D008249:Protein-Lysine 6-Oxidase / Q000032:analysis / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; C000604332:Fmod protein, mouse; D011509:Proteoglycans; D000071235:Fibromodulin; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase
keywords: collagen; cross-linking; extracellular matrix; fibromodulin; lysyl oxidase; small leucine-rich proteoglycan (SLRP)