Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 10, Pages 2917-2921Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201409135
Keywords
endergonic reactions; enzyme catalysis; hydrolysis; ligases; protein modification
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Funding
- Austrian Academy of Sciences (OAW project) [22866]
- Austrian Federal Ministry of Science, Research and Economy
- National Foundation for Research, Technology and Development
- Austrian Science Fund (FWF project) [P_23454-B11]
- Austrian Science Fund (FWF) [P23454, W1213] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 23454] Funding Source: researchfish
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Peptide ligases expand the repertoire of genetically encoded protein architectures by synthesizing new peptide bonds, energetically driven by ATP or NTPs. Here, we 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. Legumain's 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-dimensional MHC epitopes. The aspartate-aspartimide (succinimide) pair represents a new paradigm of coupling endergonic reactions in ATP-scarce environments.
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