Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFβ-binding site
Year: 2023
Type: article
Abstract: Genetic mutations in fibrillin microfibrils cause serious inherited diseases, such as Marfan syndrome 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. Here we describe a detailed structural analysis of native fibrillin microfibrils from mammalian tissue by cryogenic electron microscopy. The major bead region showed pseudo eightfold symmetry where the amino and carboxy termini reside. On the basis of this structure, we show that a WMS deletion mutation leads to the induction of a structural rearrangement that blocks interaction with latent TGFβ-binding protein-1 at a remote site. Separate deletion of this binding site resulted in the assembly of shorter fibrillin microfibrils with structural alterations. The integrin α v β 3 -binding site was also mapped onto the microfibril structure. These results establish that in complex extracellular assemblies, such as fibrillin microfibrils, mutations may have long-range structural consequences leading to the disruption of growth factor signaling and the development of disease.
Authors: Alan R. F. Godwin, Rana Dajani, Xinyang Zhang, Jennifer Thomson, David F. Holmes, Christin S. Adamo, Gerhard Sengle, Michael J. Sherratt, Alan M. Roseman, Clair Baldock
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Awards: G1021308242, G1526988638, G1642035482, FOR 2722: Neue molekulare Determinanten der Homöostase der muskuloskelettalen extrazellulären Matrix ein systemischer Ansatz, Renewal of the Wellcome Trust Centre for Cell-Matrix Research, G2047259676, TRR 259: Aortenerkrankungen, G2410120996, Renewal of the Wellcome Trust Centre for Cell-Matrix Research, G2784137354, G2791198062, G2817747440, G3038008616, G4189844723, Tissue dependent structure of fibrillin microfibrils, Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds., Dual functionalities of the LTBP family in matrix assembly and growth factor regulation, G4854761912, G5379814298, Structure and Interactions at the Cell-Matrix Interface Mediated by Collagen VI, SFB 829: Molekulare Grundlagen der Regulation der Homöostase der Haut, G6868616705, Glacios cryo-electron microscope for single particle analysis and electron tomography of proteins, complexes and fibrillar assemblies, Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds.
OpenAlex ID: W4366588851