Abstract

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