Rebecca Jernigan

New Structural Insights into the Function of the Active Full-Length Human Taspase1: A Novel Anticancer Therapeutic Target

Presented by Rebecca Jernigan (Arizona State University - Graduate Student)

Taspase1 (threonine aspartase 1) is an endopeptidase overexpressed in primary human cancers that has been identified as a novel potentially potent anticancer drug target. Loss of Taspase1 activity has been demonstrated to disrupt proliferation of human cancer cells in vitro and in mouse tumor xenograft models of glioblastoma. By functioning as a non-oncogene addiction protease, Taspase1 coordinates cancer cell proliferation, invasion and metastasis. Taspase1 encodes a highly conserved 50 kDa inactive proenzyme that undergoes auto-proteolytic cleavage becoming an active heterodimer that displays an overall αββα structure. The crystallographic structures of the proenzyme and a truncated version of activated Taspase1 are known. In this study, the crystallographic structure of the full length active human Taspase1 is shown to 3.1Å. For the first time, a key structure element has been identified: a long helix of about 50 residues that was missing in previous reported structures of the activated enzyme. Previously his helix was predicted to have a helix-turn-helix conformation lying right on top the catalytic site of Taspase1; however the crystallographic structure of the full-length taspase1 shows a straight helix conformation. This opens new insights in the enzymatic mechanisms for possible substrate recruitment of Taspsae1 and suggest the long fragment as a novel target for the design of medical drugs that inhibit the function of Taspase1 enzyme.