4N6M

Crystal structure of human cystatin E/M produced in LEXSY

Summary for 4N6M

• Entry DOI: 10.2210/pdb4n6m/pdb
• Related: 4N6L 4N6N 4N6O
• Descriptor: Cystatin-M, SULFATE ION (3 entities in total)
• Functional Keywords: cysteine protease inhibitor, legumain, asparaginyl endopeptidase, reactive center loop, papain, cathepsin, cancer, cystatin fold, protease inhibitor, hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: Q15828
• Total number of polymer chains: 2
• Total formula weight: 29943.83

Authors

Dall, E.,Brandstetter, H. (deposition date: 2013-10-14, release date: 2015-02-18, Last modification date: 2024-11-20)

Primary citation

Dall, E.,Fegg, J.C.,Briza, P.,Brandstetter, H.
Structure and mechanism of an aspartimide-dependent Peptide ligase in human legumain.
Angew.Chem.Int.Ed.Engl., 54:2917-2921, 2015

PubMed Abstract: 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.

PubMed: 25630877
DOI: 10.1002/anie.201409135

Experimental method

X-RAY DIFFRACTION (2.9 Å)