Fibrinogen assembly and secretion. Role of intrachain disulfide loops.

The Journal of Biological Chemistry
J Z Zhang, C M Redman

Abstract

Human fibrinogen is a homodimer composed of three different (Aalpha, Bbeta, gamma) polypeptide chains. The chains are linked by 29 inter- and intrachain disulfide bonds. Each half-molecule has 6 intrachain disulfide bonds, which form loops in the carboxyl-terminal region of each of the chains. Aalpha chain has one disufide loop (Cys442-Cys472), Bbeta has three (Cys201-Cys286, Cys211-Cys240, and Cys394-Cys407), and gamma has two loops (Cys153-Cys182 and Cys326-Cys339). The intrachain loops are conserved in fibrinogens of different species. We changed, by site-directed mutagenesis, the cysteines, which form the intrachain loops, to serine or alanine. Fibrinogen chain assembly and secretion was determined in transiently transfected COS cells expressing two normal and a mutant fibrinogen chain. In the Bbeta and gamma chains, disruption of the disulfide loops closest to the "coiled-coil" region (CysBbeta211-Cys240, CysBbeta201-Cys286, and Cysgamma153-Cys182) abolished chain assembly and secretion, indicating that the disulfide loops closest to the coiled-coil region are essential for chain assembly. By contrast, preventing formation of the disulfide loops, which are toward the carboxyl termini of each of the chains, had different ef...Continue Reading

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Citations

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