title: Intermolecular interactions of thrombospondins drive their accumulation in extracellular matrix.
abstract: Thrombospondins participate in many aspects of tissue organization in adult tissue homeostasis, and their dysregulation contributes to pathological processes such as fibrosis and tumor progression. The incorporation of thrombospondins into extracellular matrix (ECM) as discrete puncta has been documented in various tissue and cell biological contexts, yet the underlying mechanisms remain poorly understood. We find that collagen fibrils are disorganized in multiple tissues of Thbs1(-/-) mice. In investigating how thrombospondins become retained within ECM and thereby affect ECM organization, we find that accumulation of thrombospondin-1 or thrombospondin-5 puncta within cell-derived ECM is controlled by a novel, conserved, surface-exposed site on the thrombospondin L-type lectin domain. This site acts to recruit thrombospondin molecules into ECM by intermolecular interactions in trans. This mechanism is fibronectin independent, can take place extracellularly, and is demonstrated to be direct in vitro. The trans intermolecular interactions can also be heterotypic-for example, between thrombospondin-1 and thrombospondin-5. These data identify a novel concept of concentration-dependent, intermolecular "matrix trapping" as a conserved mechanism that controls the accumulation and thereby the functionality of thrombospondins in ECM.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Dae Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Elena D
authors.initials: ED
authors.lastname: Christofidou
authors.affiliation: Micro-Imaging Center, Shriners Hospital for Children, Portland, OR 97239.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Marwah
authors.initials: M
authors.lastname: Hassan Milde
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195 School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195 jo.adams@bristol.ac.uk.
authors.forename: Josephine C
authors.initials: JC
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002522:Chlorocebus aethiops; D003412:Cricetulus; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D024022:Fibrillar Collagens; D005353:Fibronectins / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051381:Rats; D019699:Thrombospondins / Q000378:metabolism*
chemical_list: D024022:Fibrillar Collagens; D005353:Fibronectins; D019699:Thrombospondins