Solution structure of the transforming growth factor beta -binding protein-like module, a domain associated with matrix fibrils

Abstract

Here we describe the high resolution nuclear magnetic resonance (NMR) structure of a transforming growth factor β (TGF‐β)‐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‐β‐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 β‐strands and two α‐helices. An unusual cysteine triplet conserved in the sequences of TB domains is localized to the hydrophobic core, at the C‐terminus of an α‐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‐β1 latency‐associated peptide.