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Structure of the calcium-rich signature domain of human thrombospondin-2

Nature Structural & Molecular Biology volume 12, pages 910–914 (2005)Cite this article

Abstract

Thrombospondins (THBSs) are secreted glycoproteins that have key roles in interactions between cells and the extracellular matrix. Here, we describe the 2.6-Å-resolution crystal structure of the glycosylated signature domain of human THBS2, which includes three epidermal growth factor–like modules, 13 aspartate-rich repeats and a lectin-like module. These elements interact extensively to form three structural regions termed the stalk, wire and globe. The THBS2 signature domain is stabilized by these interactions and by a network of 30 bound Ca2+ ions and 18 disulfide bonds. The structure suggests how genetic alterations of THBSs result in disease.

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Figure 1: Structure of human THBS2.
Figure 2: Ca2+ coordination in the stalk and wire elements of THBS2.
Figure 3: Disease-associated mutations or polymorphisms of THBSs mapped onto the signature domain of human THBS2.

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Acknowledgements

We thank E. Hohenester for communicating results before publication and the Advanced Photon Source beamline staff for assistance in data collection. This work was supported by US National Institutes of Health grant HL54462 to D.F.M. and a Shaw Foundation for Medical Research grant to J.L.K. C.B.C. and D.A.B. were supported by US National Institutes of Health training grants HL07899 and GM08293.

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Authors and Affiliations

  1. Department of Medicine, 4285B Medical Sciences Center and Department of Biomolecular Chemistry, 550 Medical Sciences Center, University of Wisconsin–Madison, 1300 University Avenue, Madison, 53706, Wisconsin, USA

    C Britt Carlson, Douglas S Annis, Tina M Misenheimer, Blue-leaf A Hannah & Deane F Mosher

  2. Department of Biomolecular Chemistry, 550 Medical Sciences Center, University of Wisconsin–Madison, 1300 University Avenue, Madison, 53706, Wisconsin, USA

    C Britt Carlson, Douglas A Bernstein, Deane F Mosher & James L Keck

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  1. C Britt Carlson
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  2. Douglas A Bernstein
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  3. Douglas S Annis
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  4. Tina M Misenheimer
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  7. James L Keck
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Correspondence to Deane F Mosher or James L Keck.

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Supplementary information

Supplementary Fig. 1

Stereo diagram of the human TSP-2 signature domain structure (PDF 3045 kb)

Supplementary Fig. 2

Sequence and secondary structure of the signature domain of human TSP-2 (PDF 687 kb)

Supplementary Fig. 3

Comparison of the crystal structures of the TSP-2 signature domain and the TSP-1 signature domain fragment (PDF 1918 kb)

Supplementary Table 1

TSP-2 coordination of 30 bound Ca(2+) ions (PDF 890 kb)

Supplementary Table 2

Disease-linked TSP-family mutations (PDF 1189 kb)

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Carlson, C., Bernstein, D., Annis, D. et al. Structure of the calcium-rich signature domain of human thrombospondin-2. Nat Struct Mol Biol 12, 910–914 (2005). https://doi.org/10.1038/nsmb997

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