Structural insights into the function of the catalytically active human Taspase1

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Taspase1 is a Ntn-hydrolase overexpressed in human cancers, regulating cancer cell proliferation, invasion, and metastasis.
• Loss of Taspase1 activity inhibits cancer cell proliferation in vitro and in glioblastoma mouse models.
• Taspase1 is activated through intramolecular cleavage, altering the conformation of a poorly understood C-terminal fragment.

Purpose of the Study:

• To determine the crystallographic structure of active Taspase1.
• To investigate the function of the C-terminal fragment during Taspase1 activation.
• To identify potential therapeutic targets for anticancer drug development.

Main Methods:

• Developed a cloning strategy to generate a circularly permuted form of Taspase1.
• Determined the crystallographic structure of active Taspase1.
• Assessed the role of the C-terminal region in catalytic activity.

Main Results:

• The C-terminal fragment of Taspase1 forms a long helix in the active enzyme.
• This helical region is indispensable for the catalytic activity of Taspase1.
• Structural insights into active Taspase1 were obtained.

Conclusions:

• The C-terminal helix is critical for Taspase1 enzymatic activity.
• This region represents a potential target for designing novel anticancer therapeutics.
• The findings contribute to understanding Ntn-hydrolase enzymatic mechanisms.