SOLUTION STRUCTURE OF THE TRANSFORMING-GROWTH-FACTOR BETA-BINDING PROTEIN-LIKE MODULE, A DOMAIN ASSOCIATED WITH MATRIX FIBRILS

Here we describe the high resolution nuclear magnetic resonance (NMR) structure of a transforming growth factor beta (TGF-beta)-binding prot ein-like (TB) domain, which comes from human fibrillin-1, the protein defective in the Marfan syndrome (MFS). This domain is found in fibril lins and latent TGF-beta-binding proteins (LTBPs) which are localized to fibrillar structures in the extracellular matrix, The TB domain man ifests a novel fold which is globular and comprises six antiparallel b eta-strands and two alpha-helices. An unusual cysteine triplet conserv ed in the sequences of TB domains is localized to the hydrophobic core , at the C-terminus of an alpha-helix. The structure is stabilized by four disulfide bonds which pair in a 1-3, 2-6, 4-7, 5-8 pattern, two o f which are solvent exposed, Analyses of MFS-causing mutations and the fibrillin-1 cell-binding RGD site provide the first clues to the surf ace specificity of TB domain interactions, Modelling of a homologous T B domain from LTBP-1 (residues 1018-1080) suggests that hydrophobic co ntacts may play a role in its interaction with the TGF-beta 1 latency- associated peptide.