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New Structural Insights into the Function of the Catalytically Active Human Taspase1

Nirupa Nagaratnam, Silvia L. Delker, Rebecca Jernigan, Thomas E. Edwards, Janey Snider, Darren Thifault, Dewight Williams, Brent L. Nannenga, Mary Stofega, Lidia Sambucetti, James J. Hsieh, Andrew J. Flint, Petra Fromme, Jose M. Martin-Garcia
doi: https://doi.org/10.1101/2020.11.26.400622
Nirupa Nagaratnam
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
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Silvia L. Delker
2Beryllium Discovery Corporation, Bainbridge Island, WA
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Rebecca Jernigan
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
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Thomas E. Edwards
2Beryllium Discovery Corporation, Bainbridge Island, WA
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Janey Snider
3Division of Biosciences, SRI International Menlo Park, CA, 94025
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Darren Thifault
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
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Dewight Williams
4Eyring Materials Center, Arizona State University, Tempe, AZ
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Brent L. Nannenga
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
5Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, Arizona
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Mary Stofega
3Division of Biosciences, SRI International Menlo Park, CA, 94025
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Lidia Sambucetti
3Division of Biosciences, SRI International Menlo Park, CA, 94025
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James J. Hsieh
6Molecular Oncology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO
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Andrew J. Flint
7Frederick National Lab for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD
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Petra Fromme
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
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  • For correspondence: petra.fromme@asu.edu jmmartin@iqfr.csic.es
Jose M. Martin-Garcia
1Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ
8Department of Crystallography and Structural Biology, Institute of Physical-Chemistry “Rocasolano”, Spanish National Research Council (CSIC), Madrid, Spain
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  • For correspondence: petra.fromme@asu.edu jmmartin@iqfr.csic.es
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Abstract

Proteases can play essential roles in severe human pathology, ranging from degenerative and inflammatory illnesses to infectious diseases, with some, such as Taspase1, involved in growth and progression of tumors at primary and metastatic sites. Taspase1 is a N-terminal nucleophile (Ntn)-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse xenograft models of glioblastoma, thus this protein has the potential to become a novel anticancer drug target. It belongs to the family of Ntn-hydrolases, a unique family of proteins synthesized as enzymatically inactive proenzymes that become activated upon cleavage of the peptide bond on the N-terminal side of a threonine residue, which then becomes the catalytic site nucleophile. The activation process simultaneously changes the conformation of a long domain at the C-terminus of the alpha-subunit for which no full-length structural information exists and its function is poorly understood. Here we present a novel cloning strategy to generate a fully active, circularly permuted form of Taspase1 to determine the crystallographic structure of catalytically active human Taspase1 to 3.04Å. We discovered that this region forms a long helical domain and is indispensable for the catalytic activity of Taspase1. Together, our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases and suggests that this long domain could be a novel target for the design of inhibitors with the potential to be developed into anticancer therapeutics.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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New Structural Insights into the Function of the Catalytically Active Human Taspase1
Nirupa Nagaratnam, Silvia L. Delker, Rebecca Jernigan, Thomas E. Edwards, Janey Snider, Darren Thifault, Dewight Williams, Brent L. Nannenga, Mary Stofega, Lidia Sambucetti, James J. Hsieh, Andrew J. Flint, Petra Fromme, Jose M. Martin-Garcia
bioRxiv 2020.11.26.400622; doi: https://doi.org/10.1101/2020.11.26.400622
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New Structural Insights into the Function of the Catalytically Active Human Taspase1
Nirupa Nagaratnam, Silvia L. Delker, Rebecca Jernigan, Thomas E. Edwards, Janey Snider, Darren Thifault, Dewight Williams, Brent L. Nannenga, Mary Stofega, Lidia Sambucetti, James J. Hsieh, Andrew J. Flint, Petra Fromme, Jose M. Martin-Garcia
bioRxiv 2020.11.26.400622; doi: https://doi.org/10.1101/2020.11.26.400622

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