Intermolecular interactions of thrombospondins drive their accumulation in extracellular matrix

Mol Biol Cell. 2015 Jul 15;26(14):2640-54. doi: 10.1091/mbc.E14-05-0996. Epub 2015 May 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Chlorocebus aethiops
  • Cricetulus
  • Extracellular Matrix / metabolism*
  • Female
  • Fibrillar Collagens
  • Fibronectins / metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Rats
  • Thrombospondins / metabolism*


  • Fibrillar Collagens
  • Fibronectins
  • Thrombospondins