Abstract
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) belongs to the CD clan of cysteine proteases. MALT1 is a unique enzyme among this clan because it recognizes the basic amino acid arginine in the P1 pocket. Previous studies carried out with natural amino acids revealed the substrate specificity of the P4-P1 pockets of MALT1 but have provided only limited information about the catalytic preferences of this enzyme. In this study, we exploited Hybrid Combinatorial Substrate Library and Internally Quenched Fluorescence substrate technologies to interrogate the extended substrate specificity profile of the S5-S2’ active site pockets using unnatural amino acids. This strategy resulted in the design of a peptide-based fluorogenic substrate, which exhibited significant activity toward MALT1. Subsequently, the substrate sequence was further utilized to develop potent, irreversible activity-based probes.
Highlights
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), together with caspases, separase, legumain and gingipain, belongs to the CD clan of cysteine proteases
Z-VRPR-FMK, which was originally designed as a plant metacaspase inhibitor[3], is the most frequently used MALT1 inhibitor and binds covalently to the MALT1 active site
More precise determination of the MALT1 substrate specificity was required for optimal substrate and inhibitor design
Summary
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), together with caspases, separase, legumain and gingipain, belongs to the CD clan of cysteine proteases. MALT1 contains a paracaspase domain[8]; the MALT1 S1 pocket can bind only arginine, while caspases recognize aspartic acid, and to a lesser extent glutamic acid[9,10]. This preferential hydrolysis is a function of the conformation of the surrounding active site pockets within the three-dimensional structure of the enzyme. The P5-P1 positions, optimal substrates and activity-based probes were designed, synthesized and biochemically characterized These small chemical tools could provide information about enzyme activity status in cells, physiological fluids and lysates, which could subsequently be useful in studying the role of MALT1 in physiology and disease
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