Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFβ-binding site

Abstract

Abstract Genetic mutations in fibrillin microfibrils cause serious inherited diseases such as Marfan syndrome (MFS) and Weill-Marchesani syndrome (WMS). These diseases typically show major dysregulation of tissue development and growth, particularly in skeletal long bones, but links between the mutations and the diseases are unknown. In this study, we reveal the detailed cryo-EM structure of native fibrillin microfibrils from mammalian tissue. The major bead region showed pseudo 8-fold symmetry where the N-and C-termini reside. Based on this structure, we show a WMS-deletion mutant induces a rearrangement blocking interaction with latent TGFβ-binding protein (LTBP)-1 at a remote site. Separate deletion of this binding site resulted in the assembly of shorter fibrillin microfibrils with structural alterations. The integrin αVβ3-binding site was also mapped onto the microfibril structure. These results establish that in complex extracellular assemblies, such as in fibrillin, mutations may have long-range structural consequences to disrupt growth factor signalling and cause disease.