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000894963 1001_ $$0P:(DE-HGF)0$$aDall, Elfriede$$b0$$eCorresponding author
000894963 245__ $$aThe Peptide Ligase Activity of Human Legumain Depends on Fold Stabilization and Balanced Substrate Affinities
000894963 260__ $$aWashington, DC$$bACS$$c2021
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000894963 520__ $$aProtein modification by enzymatic breaking and forming of peptide bonds significantly expands the repertoire of genetically encoded protein sequences. The dual protease-ligase legumain exerts the two opposing activities within a single protein scaffold. Primarily localized to the endolysosomal system, legumain represents a key enzyme in the generation of antigenic peptides for subsequent presentation on the MHCII complex. Here we show that human legumain catalyzes the ligation and cyclization of linear peptides at near-neutral pH conditions, where legumain is intrinsically unstable. Conformational stabilization significantly enhanced legumain’s ligase activity, which further benefited from engineering the prime substrate recognition sites for improved affinity. Additionally, we provide evidence that specific legumain activation states allow for differential regulation of its activities. Together these results set the basis for engineering legumain proteases and ligases with applications in biotechnology and drug development.
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000894963 536__ $$0G:(EU-Grant)639905$$aProPlantStress - Proteolytic processing in plant stress signal transduction and responses to abiotic stress and pathogen attack (639905)$$c639905$$fERC-2014-STG$$x1
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000894963 7001_ $$00000-0001-5924-9634$$aStanojlovic, Vesna$$b1
000894963 7001_ $$0P:(DE-Juel1)167325$$aDemir, Fatih$$b2
000894963 7001_ $$0P:(DE-HGF)0$$aBriza, Peter$$b3
000894963 7001_ $$00000-0002-0915-7579$$aDahms, Sven O.$$b4
000894963 7001_ $$0P:(DE-Juel1)162356$$aHuesgen, Pitter F.$$b5
000894963 7001_ $$00000-0002-7550-6896$$aCabrele, Chiara$$b6
000894963 7001_ $$0P:(DE-HGF)0$$aBrandstetter, Hans$$b7$$eCorresponding author
000894963 773__ $$0PERI:(DE-600)2584887-2$$a10.1021/acscatal.1c02057$$gp. 11885 - 11896$$n19$$p11885 - 11896$$tACS catalysis$$v11$$x2155-5435$$y2021
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