The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding.

Abstract	Cartilage oligomeric matrix protein (COMP), or thrombospondin-5 (TSP-5), is a secreted glycoprotein that is important for growth plate organization and function. Mutations in COMP cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). In this study, we determined the structure of a recombinant protein that contains the last epidermal growth factor repeat, the type 3 repeats and the C-terminal domain (CTD) of COMP to 3.15-A resolution limit by X-ray crystallography. The CTD is a beta-sandwich that is composed of 15 antiparallel beta-strands, and the type 3 repeats are a contiguous series of calcium binding sites that associate with the CTD at multiple points. The crystal packing reveals an exposed potential metal-ion-dependent adhesion site (MIDAS) on one edge of the beta-sandwich that is common to all TSPs and may serve as a binding site for collagens and other ligands. Disease-causing mutations in COMP disrupt calcium binding, disulfide bond formation, intramolecular interactions, or sites for potential ligand binding. The structure presented here and its unique molecular packing in the crystal identify potential interactive sites for glycosaminoglycans, integrins, and collagens, which are key to cartilage structure and function.
Authors	Kemin Tan, Mark Duquette, Andrzej Joachimiak, Jack Lawler
Journal	FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 23 Issue 8 Pg. 2490-501 (Aug 2009) ISSN: 1530-6860 [Electronic] United States
PMID	19276170 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Cartilage Oligomeric Matrix Protein DNA, Complementary Extracellular Matrix Proteins Glycoproteins Glycosaminoglycans Integrins Ligands Matrilin Proteins Oligopeptides Recombinant Proteins TSP5 protein, human Thrombospondin 1 Thrombospondins thrombospondin 2 arginyl-glycyl-aspartic acid Collagen Cysteine
Topics	Base Sequence Binding Sites Cartilage Oligomeric Matrix Protein Collagen (metabolism) Crystallography, X-Ray Cysteine (chemistry) DNA, Complementary (genetics) Extracellular Matrix Proteins (chemistry, genetics, metabolism) Glycoproteins (chemistry, genetics, metabolism) Glycosaminoglycans (metabolism) Humans In Vitro Techniques Integrins (metabolism) Ligands Matrilin Proteins Models, Molecular Mutation Oligopeptides (chemistry) Protein Binding Protein Structure, Tertiary Recombinant Proteins (chemistry, genetics, metabolism) Static Electricity Thrombospondin 1 (chemistry) Thrombospondins (chemistry)

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