Author(s)
Jose Martin-Garcia
Nirupa Nagaratnam
Silvia Delker
Rebecca Jernigan
Thomas Edwards
Janey Sneider
Darren Thifault
Dewight Williams
Brent Nannenga
Mary Stofega
Lidia Sambucetti
James J. Hsieh
Andrew Flint
Petra Fromme
Affiliation(s)
Institute of Physical Chemistry Rocasolano, CSIC;
Abstract:
Taspase1 is an Ntn-hydrolase overexpressed in primary human cancers, coordinating cancer 33Tcell proliferation, invasion, and metastasis. L33Toss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse models of glioblastoma. Taspase1 is synthesized as inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the a-subunit for which no full-length structural information exists and whose function is poorly understood. We present a novel cloning strategy to generate a circularly permuted form of Taspase1 to determine the crystallographic structure of active Taspase1. We discovered that this region forms a long helix and is indispensable for the catalytic activity of Taspase1. Our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases, suggesting that it could be a novel potential target for the design of inhibitors with potential to be developed into anticancer therapeutics.