Abstract
Taspase1 is an endoprotease that hydrolyzes the human MLL and the oncofusion protein AF4-MLL at distinct cleavage sites (CS1 and CS2). It has been demonstrated that both protein complexes require Taspase1 for protein stability and proper function. In terms of t(4;11) leukemia, Taspase1 represents a conditional oncoprotein because Taspase1 cleaves AF4-MLL to form a high molecular weight complex that causes proB ALL. Therefore, we are aiming to identify potential inhibitors against Taspase1. Unfortunately, any efforts to target the enyzmatic center of Taspase1 have failed so far. For the purpose of our studies, we have performed site-directed mutagenesis to dissect all the molecular steps which are necessary to activate Taspase1. Besides dimerization, autoproteolytic cleavage is a critical step that makes Taspase1 active. Our work has led to a working model on how Taspase1 can be allosterically inhibited. We will present our preliminary data and discuss future directions.
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