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Related Experiment Videos

Disulphide bonds assignment in the inter-alpha-inhibitor heavy chains--structural and functional implications

C Flahaut1, C Mizon, P Aumercier-Maes

  • 1Laboratoire de Biochimie, Faculté de Pharmacie, Lille, France.

European Journal of Biochemistry
|August 6, 1998
PubMed
Summary

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Human inter-alpha-inhibitor (IalphaI) is a plasma proteinase inhibitor composed of three chains. Differential susceptibility of heavy chains H1 and H2 to neutrophil proteinases is linked to their unique disulphide bonds and glycosaminoglycan interactions.

Area of Science:

  • Biochemistry
  • Proteomics
  • Structural Biology

Background:

  • Human inter-alpha-inhibitor (IalphaI) is a plasma serine-proteinase inhibitor.
  • IalphaI comprises a light chain (bikunin) and two heavy chains (H1 and H2) linked by a glycosaminoglycan.
  • Neutrophil proteinases exhibit differential susceptibility to IalphaI's heavy chains, particularly H2.

Purpose of the Study:

  • To investigate the role of disulphide bonds in the differential proteolytic susceptibility of IalphaI heavy chains (H1 and H2).
  • To elucidate the structural differences between H1 and H2 heavy chains contributing to their varied protease interactions.

Main Methods:

  • Disulphide bond mapping using amino acid sequencing and mass spectrometry.
  • Limited proteolysis with Staphylococcus aureus V-8 proteinase.

Related Experiment Videos

  • Circular dichroism (CD) analysis for conformational and aromatic amino acid environment assessment.

    • Main Results:

    • Heavy chain H1 possesses one free thiol group and two disulphide bridges, one linking distant cysteine residues (Cys239-Cys511).
    • Heavy chain H2 contains two disulphide bonds between closely located cysteine residues.
    • Despite structural differences, both H1 and H2 are similarly susceptible to Staphylococcus aureus V-8 proteinase, with cleavage at the N-terminus.
    • CD analysis indicates similar polypeptide backbone conformations but different aromatic amino acid environments in H1 and H2.
    • Heavy chains are linked to the glycosaminoglycan via their C-terminal aspartic acid residue.

    Conclusions:

    • The distinct disulphide topology of IalphaI heavy chains H1 and H2 contributes to their differential susceptibility to neutrophil proteinases.
    • The affinity of cationic neutrophil proteinases for the anionic glycosaminoglycan likely mediates preferential cleavage of heavy chains, especially H2, near the C-terminus.
    • Structural variations in disulphide bonding and glycosaminoglycan interactions dictate IalphaI's proteolytic susceptibility.