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  • The EMBO Journal (2004) 23, 1223 - 1233
  • doi:10.1038/sj.emboj.7600166

Published online: 11 March 2004

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

Marc Kvansakul1, Josephine C Adams2 and Erhard Hohenester1

  1. Department of Biological Sciences, Imperial College London, South Kensington Campus, London, UK
  2. Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Correspondence to:

Erhard Hohenester, Biophysics Group, Blackett Laboratory, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. Tel.: +44 20 7594 7701; Fax: +44 20 7589 0191; E-mail: e.hohenester@imperial.ac.uk

Received 6 October 2003; Accepted 19 February 2004

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.

  • Keywords:

    • calcium binding,
    • cell adhesion,
    • extracellular matrix,
    • L-type lectin,
    • protein folding