Mutations in fibrillin‐1 leading to classical and neonatal Marfan syndrome cause differential protease susceptibilities and protein function

TL;DRAbstract

Fibrillin‐1 constitutes the backbone of extracellular matrix microfibrils, which are crucial for regulating elastic fiber biogenesis and TGF‐beta bioavailability. Mutations in fibrillin‐1 give rise to the Marfan syndrome (MFS) characterized by vascular, skeletal and ocular symptoms. To investigate molecular consequences of mutations causing severe neonatal or the milder classical form of MFS, point mutations from each group were introduced in recombinant human fibrillin‐1 fragments. Proteolytic susceptibility was probed with physiological and non‐physiological proteases. The mutant proteins harboring neonatal mutations were typically more susceptible to proteolytic cleavage than those with classic mutations. The cleavage sites were found both in close proximity and distant to the mutations, indicating structural changes and the exposure of cryptic cleavage sites. The group of neonatal mutations more severely affected the ability of fibrillin‐1 to interact with heparin/heparan sulfate,

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