Structure of a thrombospondin C-terminal fragment reveals a novel calcium core in the type 3 repeats

EMBO J. 2004 Mar 24;23(6):1223-33. doi: 10.1038/sj.emboj.7600166. Epub 2004 Mar 11.


Thrombospondins (TSPs) are extracellular regulators of cell-matrix interactions and cell phenotype. The most highly conserved region of all TSPs are the calcium-binding type 3 (T3) repeats and the C-terminal globular domain (CTD). The crystal structure of a cell-binding TSP-1 fragment, spanning three T3 repeats and the CTD, reveals a compact assembly. The T3 repeats lack secondary structure and are organised around a core of calcium ions; two DxDxDGxxDxxD motifs per repeat each encapsulate two calcium ions in a novel arrangement. The CTD forms a lectin-like beta-sandwich and contains four strictly conserved calcium-binding sites. Disruption of the hairpin structure of T3 repeats 6 and 7 decreases protein secretion and stability. The availability for cell attachment of an RGD motif in T3 repeat 7 is modulated by calcium loading. The central architectural role of calcium explains how it is critical for the functions of the TSP C-terminal region. Mutations in the T3 repeats of TSP-5/COMP, which cause two human skeletal disorders, are predicted to disrupt the tertiary structure of the T3-CTD assembly.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium / metabolism*
  • Cell Adhesion
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Repetitive Sequences, Amino Acid*
  • Sequence Alignment
  • Thrombospondin 1 / chemistry*
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / metabolism*


  • Oligopeptides
  • Peptide Fragments
  • Thrombospondin 1
  • arginyl-glycyl-aspartic acid
  • Calcium