1u5m

From Proteopedia

Revision as of 12:27, 20 March 2008

Structure of a Chordin-like Cysteine-rich Repeat (VWC module) from Collagen IIA

Overview

Chordin-like cysteine-rich (CR) repeats (also referred to as von Willebrand factor type C (VWC) modules) have been identified in approximately 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-beta (TGF-beta) 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-beta1 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 beta-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.

Disease

Known diseases associated with this structure: Achondrogenesis-hypochondrogenesis, type II OMIM:[120140], Epiphyseal dysplasia, multiple, with myopia and deafness OMIM:[120140], Kniest dysplasia OMIM:[120140], Osteoarthrosis OMIM:[120140], SED congenita OMIM:[120140], SED, Namaqualand type OMIM:[120140], SMED Strudwick type OMIM:[120140], Spondyloperipheral dysplasia OMIM:[120140], Stickler syndrome, type I OMIM:[120140], Vitreoretinopathy with phalangeal epiphyseal dysplasia ( OMIM:[120140]

About this Structure

1U5M is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Solution structure and dynamics of a prototypical chordin-like cysteine-rich repeat (von Willebrand Factor type C module) from collagen IIA., O'Leary JM, Hamilton JM, Deane CM, Valeyev NV, Sandell LJ, Downing AK, J Biol Chem. 2004 Dec 17;279(51):53857-66. Epub 2004 Oct 1. PMID:15466413

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