TY - JOUR
T1 - Solution structure and dynamics of a prototypical chordin-like cysteine-rich repeat (von Willebrand factor type C module) from collagen IIA
AU - O'Leary, Joanne M.
AU - Hamilton, John U.
AU - Deane, Charlotte M.
AU - Valeyev, Najl V.
AU - Sandell, Linda J.
AU - Downing, A. Kristina
PY - 2004/12/17
Y1 - 2004/12/17
N2 - 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-β (TGF-β) 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 (CRColIIA), which has been previously shown to bind TGF-β1 and bone morphogenetic protein-2. The CRColIIA structure manifests a two sub-domain architecture tethered by a flexible linkage. Initial structures were calculated using RosettaNMR, a de nova prediction method, and final structure calculations were performed using CANDID within CYANA. The N-terminal region contains mainly β-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 time-scale 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.
AB - 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-β (TGF-β) 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 (CRColIIA), which has been previously shown to bind TGF-β1 and bone morphogenetic protein-2. The CRColIIA structure manifests a two sub-domain architecture tethered by a flexible linkage. Initial structures were calculated using RosettaNMR, a de nova prediction method, and final structure calculations were performed using CANDID within CYANA. The N-terminal region contains mainly β-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 time-scale 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.
UR - http://www.scopus.com/inward/record.url?scp=11144240469&partnerID=8YFLogxK
U2 - 10.1074/jbc.M409225200
DO - 10.1074/jbc.M409225200
M3 - Article
C2 - 15466413
AN - SCOPUS:11144240469
SN - 0021-9258
VL - 279
SP - 53857
EP - 53866
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 51
ER -