EFFECT OF MARFAN MUTATIONS ON FIBRILLIN-1 C-PROPEPTIDE

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Fibrillin-1 is a large extracellular glycoprotein which is the major structural component of 10 nm diameter microfibrils. The Marfan syndrome, characterized by severe cardiovascular, skeletal and ocular 'abnormalities, is caused by mutations in the fibrillin-l gene. Whether Marfan mutations can directly affect assembly of fibrillin microfibrils is unknown. In order to investigate the effect of Marfan mutations in the fibrillin-1 C-terminal propeptide, we have recombinantly expressed a wildtype C-terminal peptide and the same domain containing premature termination codons (W2756X and R2776X). These mutations occur C-terminal to a furin consensus cleavage site. Therefore, after proteolytic processing of the propeptide, mature fibrillin molecules translated from these mutant alleles would be predicted to be normal. We have also expressed a construct which lacks the C-propeptide, terminating at the predicted furin cleavage site. We have investigated the effects of the Marfan mutations and the truncated C-terminus on secretion, disulfide bond formation, and processing, compared to the wildtype C-propeptide. Recombinant wildtype peptides and peptides containing Marfan mutations are properly processed, as predicted. The wildtype peptides and truncated C-terminal peptides are secreted as monomers into the media. However, during purification, whereas the wildtype peptides remain monomeric, the truncated C-terminal peptides also form reducible and nonreducible high molecular weight complexes. These results suggest that the function of the C-propeptide may be to prevent abnormal interactions within the mature C-terminal domain.
日本結合組織学会の論文

EFFECT OF MARFAN MUTATIONS ON FIBRILLIN-1 C-PROPEPTIDE

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