title: Structure and mechanism of an aspartimide-dependent peptide ligase in human legumain.
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.
authors: Department of Molecular Biology, University of Salzburg, 5020 Salzburg (Austria).
authors: Elfriede
authors: E
authors: Dall
authors: Julia C
authors: JC
authors: Fegg
authors: Peter
authors: P
authors: Briza
authors: Hans
authors: H
authors: Brandstetter
mesh_terms: D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006801:Humans; D008025:Ligases / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D000099240:Asparaginyl Endopeptidase
chemical_list: D001224:Aspartic Acid; D003546:Cysteine Endopeptidases; D008025:Ligases; D000099240:Asparaginyl Endopeptidase; C075871:aspartimide
keywords: endergonic reactions; enzyme catalysis; hydrolysis; ligases; protein modification
references: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12461-6
references: 15314233
references: J Biol Chem. 2014 May 23;289(21):14488-9
references: 24695739
references: Biochemistry. 1991 Apr 30;30(17):4151-9
references: 2021606
references: FEBS Lett. 1991 Dec 2;294(1-2):89-93
references: 1743299
references: Science. 1994 Oct 14;266(5183):243-7
references: 7939659
references: Mol Cells. 1998 Oct 31;8(5):503-12
references: 9856335
references: Nature. 1998 Dec 17;396(6712):695-9
references: 9872320
references: J Biol Chem. 1999 Jul 2;274(27):19195-203
references: 10383426
references: Science. 1999 Jul 30;285(5428):760-3
references: 10427003
references: Free Radic Res. 1999 Oct;31(4):325-34
references: 10517537
references: Biochem J. 2004 Dec 1;384(Pt 2):201-32
references: 15450003
references: J Bacteriol. 2005 Aug;187(15):5195-202
references: 16030213
references: Genes Immun. 2005 Aug;6(5):452-6
references: 15875056
references: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):468-73
references: 19106291
references: BMC Cancer. 2010;10:17
references: 20074384
references: J Exp Med. 2011 Apr 11;208(4):643-51
references: 21402738
references: J Biol Chem. 2011 Nov 4;286(44):38321-8
references: 21832066
references: Nature. 2011 Dec 22;480(7378):471-9
references: 22193101
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Jan 1;68(Pt 1):24-31
references: 22232165
references: J Cell Biochem. 2012 Aug;113(8):2679-86
references: 22441772
references: PLoS Pathog. 2012;8(8):e1002841
references: 22916010
references: PLoS One. 2013;8(1):e52980
references: 23326369
references: Biochim Biophys Acta. 2000 Mar 7;1477(1-2):241-52
references: 10708861
references: Mol Cell. 2003 Feb;11(2):543-9
references: 12620240
references: Immunity. 2003 Apr;18(4):489-98
references: 12705852
references: J Med Chem. 2004 Apr 8;47(8):1889-92
references: 15055989
references: World J Urol. 2013 Apr;31(2):359-64
references: 23124822
references: J Biol Chem. 2013 Jun 14;288(24):17495-507
references: 23640887
references: Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):10940-5
references: 23776206
references: Curr Opin Chem Biol. 2013 Aug;17(4):546-54
references: 23809361
references: Cell Res. 2014 Mar;24(3):344-58
references: 24407422
references: FEBS Lett. 1989 Jan 30;243(2):234-8
references: 2917648