Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Genetic mutations in fibrillin microfibrils are linked to inherited disorders such as Marfan syndrome and Weill-Marchesani syndrome (WMS).
• These conditions cause significant dysregulation in tissue development and growth, particularly in skeletal long bones.
• The precise molecular mechanisms connecting fibrillin mutations to these diseases remain largely unknown.

Purpose of the Study:

• To conduct a detailed structural analysis of native fibrillin microfibrils using cryogenic electron microscopy.
• To elucidate the structural consequences of disease-associated mutations in fibrillin.
• To understand how fibrillin microfibril structure impacts extracellular matrix assembly and growth factor signaling.

Main Methods:

• Cryogenic electron microscopy (cryo-EM) for high-resolution structural analysis of native mammalian fibrillin microfibrils.
• Structural analysis of microfibrils with specific deletion mutations associated with Weill-Marchesani syndrome (WMS).
• Mapping of binding sites for latent TGFβ-binding protein-1 and integrin αvβ3.

Main Results:

• The major bead region of fibrillin microfibrils exhibits pseudo eightfold symmetry, housing the amino and carboxy termini.
• A WMS deletion mutation induces a long-range structural rearrangement, blocking latent TGFβ-binding protein-1 interaction at a remote site.
• Deletion of the latent TGFβ-binding protein-1 site leads to shorter fibrillin microfibrils with altered structures; the integrin αvβ3 binding site was also mapped.

Conclusions:

• Mutations in fibrillin microfibrils can cause distant structural rearrangements with significant functional consequences.
• These structural changes disrupt critical growth factor signaling pathways, contributing to the pathogenesis of inherited connective tissue diseases.
• Understanding the structure-function relationship of fibrillin microfibrils is crucial for deciphering disease mechanisms and developing potential therapeutic strategies.