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

Structure of a thrombospondin C‐terminal fragment reveals a novel calcium core in the type 3... 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 β‐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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

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

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1038/sj.emboj.7600166
Publisher site
See Article on Publisher Site

Abstract

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 β‐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.

Journal

The EMBO JournalWiley

Published: Dec 24, 2005

Keywords: ; ; ; ;

References

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