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Fibrinogen assembly and secretion. Role of intrachain disulfide loops

J Z Zhang1, C Redman

  • 1Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021, USA.

The Journal of Biological Chemistry
|November 22, 1996
PubMed

Insights

Disulfide loops in human fibrinogen

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Protein Structure

Background:

  • Human fibrinogen is a complex protein essential for blood clotting.
  • It consists of three polypeptide chains (Aalpha, Bbeta, gamma) linked by disulfide bonds.
  • Intrachain disulfide bonds form loops within each chain, conserved across species.

Purpose of the Study:

  • To investigate the role of intrachain disulfide loops in fibrinogen assembly and secretion.
  • To determine which specific disulfide loops are critical for these processes.

Main Methods:

  • Site-directed mutagenesis was used to alter cysteine residues forming disulfide loops in fibrinogen chains.
  • Mutant and normal fibrinogen chains were expressed in COS cells.
  • Chain assembly and secretion were analyzed in transfected cells.

Main Results:

  • Disrupting disulfide loops near the coiled-coil region of Bbeta and gamma chains abolished chain assembly and secretion.
  • Disrupting the Aalpha disulfide loop or the BbetaCys394-Cys407 loop had no significant effect on assembly or secretion.
  • Disrupting the Cysgamma326-Cys339 loop allowed assembly but prevented secretion.

Conclusions:

  • Disulfide loops closest to the coiled-coil region are essential for proper fibrinogen chain assembly.
  • Disulfide loops located towards the carboxyl termini have varied roles, with Cysgamma326-Cys339 being critical for secretion post-assembly.

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