@article{23e0c309fd6b4b68ab8117ee160ee958,
title = "Structural insights into the function of the catalytically active human Taspase1",
abstract = "Taspase1 is an 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 models of glioblastoma. Taspase1 is synthesized as an inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the α subunit, for which no full-length structural information exists and whose function is poorly understood. We present a 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 potential target for the design of inhibitors with potential to be developed into anticancer therapeutics.",
keywords = "Ntn-hydrolases, Taspase1, X-ray crystallography, anisotropy, cancer, intrinsically disordered proteins, plant-type L-asparaginases, proteases",
author = "Nirupa Nagaratnam and Delker, {Silvia L.} and Rebecca Jernigan and Edwards, {Thomas E.} and Janey Snider and Darren Thifault and Dewight Williams and Nannenga, {Brent L.} and Mary Stofega and Lidia Sambucetti and Hsieh, {James J.} and Flint, {Andrew J.} and Petra Fromme and Martin-Garcia, {Jose M.}",
note = "Funding Information: This project has been funded in whole with Federal funds from the National Cancer Institute (NCI) , National Institutes of Health (NIH) , under Chemical Biology Consortium contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We would like to recognize the protein expression, purification, and crystallization teams at Beryllium for their assistance. We thank Philip Choi and Liang Tong for providing the two-chain versions of Taspase1 used in some of the enzyme assays. We thank Dr. Barbara Mroczkowski, Dr. Joel Schneider, and Dr. Michele Zacks, for their careful scientific editing and proofreading. Funding Information: This project has been funded in whole with Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Chemical Biology Consortium contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. We would like to recognize the protein expression, purification, and crystallization teams at Beryllium for their assistance. We thank Philip Choi and Liang Tong for providing the two-chain versions of Taspase1 used in some of the enzyme assays. We thank Dr. Barbara Mroczkowski, Dr. Joel Schneider, and Dr. Michele Zacks, for their careful scientific editing and proofreading. Conceptualization, J.M.M.-G. S.L.D. T.E.E. P.F. A.J.F. and J.J.H.; methodology, J.M.M.-G. S.L.D. T.E.E. P.F. A.J.F. and J.J.H.; formal analysis, J.M.M.-G. N.N. S.L.D. T.E.E. and D.T.; investigation, J.M.M.-G. N.N. S.L.D. R.J. T.E.E. L.S. M.S. J.S. D.W. and B.N.; writing ? original draft, J.M.M.-G. P.F. A.J.F. N.N. R.J. L.S. S.L.D. and J.S.; writing ? review & editing, J.M.M.-G. P.F. A.J.F. N.N. L.S. S.L.D. and J.S.; supervision, J.M.M.-G. P.F. and A.J.F.; funding acquisition, P.F. and A.J.F.; project administration, A.J.F. and J.J.H. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
month = aug,
day = "5",
doi = "10.1016/j.str.2021.03.008",
language = "English",
volume = "29",
pages = "873--885.e5",
journal = "Structure",
issn = "0969-2126",
number = "8",
}