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J. Biol. Chem., Vol. 279, Issue 51, 53857-53866, December 17, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/51/53857    most recent M409225200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O'Leary, J. M. Articles by Downing, A. K. Search for Related Content PubMed PubMed Citation Articles by O'Leary, J. M. Articles by Downing, A. K. Social Bookmarking                      What's this?

Solution Structure and Dynamics of a Prototypical Chordin-like Cysteine-rich Repeat (von Willebrand Factor Type C Module) from Collagen IIA^*

Joanne M. O'Leary, John M. Hamilton, Charlotte M. Deane, Najl V. Valeyev¶, Linda J. Sandell||, and A. Kristina Downing, A Wellcome Trust Senior Research Fellow (Grant 057725)**

From the Division of Structural Biology, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, the Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, United Kingdom, and the ^||Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri 63110

Chordin-like cysteine-rich (CR) repeats (also referred to as von Willebrand factor type C (VWC) modules) have been identified in 200 extracellular matrix proteins. These repeats, named on the basis of amino acid conservation of 10 cysteine residues, have been shown to bind members of the transforming growth factor- (TGF-) superfamily and are proposed to regulate growth factor signaling. Here we describe the intramolecular disulfide bonding, solution structure, and dynamics of a prototypical chordin-like CR repeat from procollagen IIA (CR_ColIIA), which has been previously shown to bind TGF-1 and bone morphogenetic protein-2. The CR_ColIIA structure manifests a two sub-domain architecture tethered by a flexible linkage. Initial structures were calculated using RosettaNMR, a de novo prediction method, and final structure calculations were performed using CANDID within CYANA. The N-terminal region contains mainly -sheet and the C-terminal region is more irregular with the fold constrained by disulfide bonds. Mobility between the N- and C-terminal sub-domains on a fast timescale was confirmed using NMR relaxation measurements. We speculate that the mobility between the two sub-domains may decrease upon ligand binding. Structure and sequence comparisons have revealed an evolutionary relationship between the N-terminal sub-domain of the CR module and the fibronectin type 1 domain, suggesting that these domains share a common ancestry. Based on the previously reported mapping of fibronectin binding sites for vascular endothelial growth factor to regions containing fibronectin type 1 domains, we discuss the possibility that this structural homology might also have functional relevance.

Received for publication, August 11, 2004 , and in revised form, September 21, 2004.

The atomic coordinates and structure factors (code 1U5M) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This research was supported in part by Wellcome Trust Project Grant 065450. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A Wellcome Trust Prize Student (Grant 070417).

^** To whom correspondence should be addressed: Tel.: 44-(0)1865-285322; Fax: 44-(0)1865-285323; E-mail: kristy.downing{at}bioch.ox.ac.uk.

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