title: Enhanced activity of transforming growth factor β1 (TGF-β1) bound to cartilage oligomeric matrix protein.
abstract: Cartilage oligomeric matrix protein (COMP) is an important non-collagenous cartilage protein that is essential for the structural integrity of the cartilage extracellular matrix. The repeated modular structure of COMP allows it to "bridge" and assemble multiple cartilage extracellular matrix components such as collagens, matrilins, and proteoglycans. With its modular structure, COMP also has the potential to act as a scaffold for growth factors, thereby affecting how and when the growth factors are presented to cell-surface receptors. However, it is not known whether COMP binds growth factors. We studied the binding interaction between COMP and TGF-β1 in vitro and determined the effect of COMP on TGF-β1-induced signal transduction in reporter cell lines and primary cells. Our results demonstrate that mature COMP protein binds to multiple TGF-β1 molecules and that the peak binding occurs at slightly acidic pH. These interactions were confirmed by dual polarization interferometry and visualized by rotary shadow electron microscopy. There is cation-independent binding of TGF-β1 to the C-terminal domain of COMP. In the presence of manganese, an additional TGF-β-binding site is present in the TSP3 repeats of COMP. Finally, we show that COMP-bound TGF-β1 causes increased TGF-β1-dependent transcription. We conclude that TGF-β1 binds to COMP and that TGF-β1 bound to COMP has enhanced bioactivity.
authors.affiliation: Lawrence J. Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, University of California Davis Medical Center, Sacramento, California 95817, USA. dominik.haudenschild@ucdmc.ucdavis.edu
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Haudenschild
authors.forename: Eunmee
authors.initials: E
authors.lastname: Hong
authors.forename: Jasper H N
authors.initials: JH
authors.lastname: Yik
authors.forename: Brett
authors.initials: B
authors.lastname: Chromy
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Kaylene D
authors.initials: KD
authors.lastname: Snow
authors.forename: Chitrangada
authors.initials: C
authors.lastname: Acharya
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.forename: Paul E
authors.initials: PE
authors.lastname: Di Cesare
mesh_terms: D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D064235:Matrilin Proteins; D046529:Microscopy, Electron, Transmission; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D053773:Transforming Growth Factor beta1