title: Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins.
abstract: The fibrillins and latent transforming growth factor-beta binding proteins (LTBPs) form a superfamily of structurally-related proteins consisting of calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with 8-cysteine-containing transforming growth factor beta-binding protein-like (TB) and hybrid (hyb) domains. Fibrillins are the major components of the extracellular 10-12 nm diameter microfibrils, which mediate a variety of cell-matrix interactions. Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 A resolution. The hybrid domain fold is similar, but not identical, to the TB domain fold seen in previous fibrillin-1 and LTBP-1 fragments. Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca(2+) binding. These observations provide accurate constraints for models of fibrillin organization within the 10-12 nm microfibrils and provide further molecular insights into how Ca(2+) binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford, UK.
authors.forename: Sacha A
authors.initials: SA
authors.lastname: Jensen
authors.forename: Sarah
authors.initials: S
authors.lastname: Iqbal
authors.forename: Edward D
authors.initials: ED
authors.lastname: Lowe
authors.forename: Christina
authors.initials: C
authors.lastname: Redfield
authors.forename: Penny A
authors.initials: PA
authors.lastname: Handford
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000737:chemistry / Q000378:metabolism; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D002135:Calcium-Binding Proteins; D004220:Disulfides; D016228:Endothelial Growth Factors; D000071837:Fibrillins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D002118:Calcium