CCS researchers uncover new function of the cancer protease legumain
The Brandstetter lab identified an as far unknown ligase activity of legumain, an protease frequently overexpressed in a variety of human cancers.
Peptide ligases expand the repertoire of genetically encoded protein architectures by synthesizing new peptide bonds, energetically driven by ATP or NTPs. In the present study, Dall et al. report the discovery of a genuine ligase activity in human legumain (AEP) which has important roles in immunity and tumor progression that were believed to be due to its established cysteine protease activity. Defying dogma, the ligase reaction is independent of the catalytic cysteine but exploits an endogenous energy reservoir that results from the conversion of a conserved aspartate to a metastable aspartimide. Legumains dual protease–ligase activities are pH- and thus localization controlled, dominating at acidic and neutral pH, respectively. Their relevance includes reversible on–off switching of cystatin inhibitors and enzyme (in)activation, and may affect the generation of three-dimensionalMHCepitopes. The aspartate– aspartimide (succinimide) pair represents a new paradigm of coupling endergonic reactions in ATP-scarce environments.
The study by Dall et al. appeared in the latest issue of Angewandte Chemie (International Edition).