title: The Tyrosine Sulfate Domain of Fibromodulin Binds Collagen and Enhances Fibril Formation.
abstract: Small leucine-rich proteoglycans interact with other extracellular matrix proteins and are important regulators of matrix assembly. Fibromodulin has a key role in connective tissues, binding collagen through two identified binding sites in its leucine-rich repeat domain and regulating collagen fibril formation in vitro and in vivo Some nine tyrosine residues in the fibromodulin N-terminal domain are O-sulfated, a posttranslational modification often involved in protein interactions. The N-terminal domain mimics heparin, binding proteins with clustered basic amino acid residues. Because heparin affects collagen fibril formation, we investigated whether tyrosine sulfate is involved in fibromodulin interactions with collagen. Using full-length fibromodulin and its N-terminal tyrosine-sulfated domain purified from tissue, as well as recombinant fibromodulin fragments, we found that the N-terminal domain binds collagen. The tyrosine-sulfated domain and the leucine-rich repeat domain both bound to three specific sites along the collagen type I molecule, at the N terminus and at 100 and 220 nm from the N terminus. The N-terminal domain shortened the collagen fibril formation lag phase and tyrosine sulfation was required for this effect. The isolated leucine-rich repeat domain inhibited the fibril formation rate, and full-length fibromodulin showed a combination of these effects. The fibrils formed in the presence of fibromodulin or its fragments showed more organized structure. Fibromodulin and its tyrosine sulfate domain remained bound on the formed fiber. Taken together, this suggests a novel, regulatory function for tyrosine sulfation in collagen interaction and control of fibril formation.
authors.affiliation: From the Departments of Clinical Sciences Lund, Rheumatology and Molecular Skeletal Biology BMC-C12 and.
authors.forename: Viveka
authors.identifier: http://orcid.org/0000-0003-2869-9477
authors.initials: V
authors.lastname: Tillgren
authors.affiliation: Clinical Sciences Lund, Division of Infection Medicine (BMC) BMC-B14, Lund University, SE-22184 Lund, Sweden.
authors.forename: Matthias
authors.identifier: http://orcid.org/0000-0001-7018-515X
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: From the Departments of Clinical Sciences Lund, Rheumatology and Molecular Skeletal Biology BMC-C12 and.
authors.forename: Patrik
authors.identifier: http://orcid.org/0000-0002-2345-2937
authors.initials: P
authors.lastname: Önnerfjord
authors.affiliation: From the Departments of Clinical Sciences Lund, Rheumatology and Molecular Skeletal Biology BMC-C12 and.
authors.forename: Sebastian
authors.identifier: http://orcid.org/0000-0002-6600-9302
authors.initials: S
authors.lastname: Kalamajski
authors.affiliation: From the Departments of Clinical Sciences Lund, Rheumatology and Molecular Skeletal Biology BMC-C12 and Anders.Aspberg@med.lu.se.
authors.forename: Anders
authors.identifier: http://orcid.org/0000-0002-6588-6944
authors.initials: A
authors.lastname: Aspberg
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism*; D000071235:Fibromodulin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D011994:Recombinant Proteins; D000071235:Fibromodulin; C005662:tyrosine O-sulfate; D014443:Tyrosine
keywords: collagen; extracellular matrix; fibrillogenesis; fibromodulin; post-translational modification (PTM); protein assembly; tyrosine sulfation