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Updated: Aug 14, 2026

Protein Transfection of Mouse Lung
04:21

Protein Transfection of Mouse Lung

Published on: May 15, 2013

Hepatocyte growth factor activator inhibitor-2 rapidly inactivates airway-expressed human type II transmembrane

Bryan J Fraser1, Ryan P Wilson2, Jackie Lac2

  • 1Structural Genomics Consortium Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

The Journal of Biological Chemistry
|August 12, 2026
PubMed

Insights

Hepatocyte growth factor activator inhibitor-2 (HAI-2) inactivates human transmembrane serine proteases (TTSPs) like TMPRSS2 after zymogen activation. This discovery offers a basis for developing HAI-2 based antivirals and anti-cancer therapeutics.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Human Type II Transmembrane Serine Proteases (TTSPs) are critical for viral entry and cancer metastasis.
  • Natural inhibition mechanisms for TTSPs are not fully understood.
  • Hepatocyte growth factor activator inhibitor-2 (HAI-2) is a known inhibitor of TMPRSS2, a key TTSP.

Purpose of the Study:

  • To elucidate the mechanism by which HAI-2 regulates TTSP activity.
  • To investigate HAI-2's interaction with activated TTSPs.
  • To explore the therapeutic potential of HAI-2 for viral infections and cancer.

Main Methods:

  • Biochemical and biophysical assays were used to study HAI-2 and TTSP interactions.
  • Mutagenesis and ligand binding assays were performed.
  • Inhibition assays were conducted using various proteases and HAI-2 constructs.

Main Results:

  • HAI-2 effectively inactivates TMPRSS2 and other TTSPs post-zymogen activation.
  • Kunitz domains 1 and 2 of HAI-2 form stable complexes with TTSPs, but not via the typical Laskowski mechanism.
  • HAI-2 does not inhibit thrombin, and multivalent HAI-2 proteins show high potency against TMPRSS2.

Conclusions:

  • HAI-2 regulates TTSP activity through a unique mechanism after protease activation.
  • Understanding this mechanism provides a foundation for developing HAI-2-based therapeutics.
  • Engineered HAI-2 proteins could serve as novel antivirals and anti-cancer agents.
Keywords:
Kunitz Domainantiviralenzyme inactivatorenzyme regulationprotease inhibitorserine proteasestransmembrane

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