Direct capping of human pulps with a dentin bonding system or with calcium. These data strongly suggest that structural and functional modifications as well as degradation processes of fibrillin-1 in the connective tissues of patients with homocystinuria play a major role in the pathogenesis of this disorder. Hrsted-Bindslev P, Vilkinis V, Sidlauskas A. Furthermore, data were obtained demonstrating that homocysteine can covalently modify fibrillin-1 via disulfide bonds. Formalin-fixed and paraffin embedded Rat liver labeled with Anti-FBN1/fibrillin 1 Polyclonal Antibody, Unconjugated (bs-1157R) at 1:200 followed by conjugation to the secondary antibody and DAB staining. Incubation of the recombinant proteins with homocysteine rendered the analyzed calcium binding EGF domains as well as the 8-Cys/transforming growth factor-beta binding domain 3 significantly more susceptible to proteolytic degradation. Calcium binding of homocysteine-modified fragments was completely abolished. Equilibrium dialysis demonstrated a number of high affinity calcium binding sites in the tandemly repeated calcium binding epidermal growth factor-like domains 11-22. Circular dichroism spectroscopy revealed moderate changes of their secondary structures after incubation with homocysteine. The presence of calcium ions in the ECM embued fibrillin with resistance to proteolytic enzymes such as trypsin, matrix metalloproteinases and plasmin 47, 48. To test this hypothesis we produced recombinant human fibrillin-1 fragments spanning the central portion of the molecule (8-Cys/transforming growth factor-beta binding domain 3 to calcium binding EGF domain 22) and extensively analyzed the potential of homocysteine to modify structural and functional properties of these proteins. Finally, calcium plays important role in fibrillin interactions with several matrix proteins including versican, aggrecan, fibulins and HSPGs 43,44,45,46. These observations led to the hypothesis that the structure and function of fibrillin-1 is compromised in patients with homocystinuria. Many abnormalities in the connective tissue of patients with homocystinuria resemble those seen in Marfan syndrome, caused by mutations in fibrillin-1. Most patients have a defect in the cystathionine-beta-synthase, the key enzyme in the conversion of homocysteine to cysteine. Forty-three of the EGF domains have a calcium binding (cb) motif and are arranged in. Homocystinuria, a disorder originating in defects in the methionine metabolism, is characterized by an elevated plasma concentration of homocysteine. The modular architecture of fibrillin-1 is dominated by EGF and TB domains.
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