New fibrinogen substitution (ySer313Arg) causes diminished y chain expression and hypodysfibrinogenaemia

摘要

Fibrinogen, also known as factor I, is an integral component of the haemostatic system occupying centre stage in both the coagulation and fibrinolytic pathways. The mature 340 kDa molecule is a dimer of three poly-peptide chains (A alpha B beta gamma)_2 arranged in a tri-nodular D-E-D structure. The central E domain is formed from the N-termini of all six chains and the outer D domains from the independently folding C-terminal regions of both the Bbeta and gamma chains. Cleavage of the N-terminal A peptide exposes a positively charged GPR- sequence which docks with a pre-existing negative binding pocket located in the yD region of a neighbouring molecule. This same gamma D region is also directly involved in inter molecular D-D interactions, Ca~(2+) binding, factor XIII mediated cross-linking and platelet binding via the terminal -AGDV sequence (1). Proper folding of the yD domain is therefore essential for maintaining functionality (2), but it is also necessary for molecular assembly and the export of the mature protein from the hepatocyte (3, 4). We report here the identification of a novel y313Ser->Arg substitution in the yD domain that effects both expression level and fibrinogen function.