Universität zu Köln

Dall, Elfriede, Stanojlovic, Vesna, Demir, Fatih, Briza, Peter, Dahms, Sven O., Huesgen, Pitter F., Cabrele, Chiara ORCID: 0000-0002-7550-6896 and Brandstetter, Hans ORCID: 0000-0002-6089-3045 (2021). The Peptide Ligase Activity of Human Legumain Depends on Fold Stabilization and Balanced Substrate Affinities. ACS Catal., 11 (19). S. 11885 - 11897. WASHINGTON: AMER CHEMICAL SOC. ISSN 2155-5435

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Abstract

Protein 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dall, Elfriede UNSPECIFIED UNSPECIFIED UNSPECIFIED Stanojlovic, Vesna UNSPECIFIED UNSPECIFIED UNSPECIFIED Demir, Fatih UNSPECIFIED UNSPECIFIED UNSPECIFIED Briza, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahms, Sven O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Huesgen, Pitter F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabrele, Chiara UNSPECIFIED orcid.org/0000-0002-7550-6896 UNSPECIFIED Brandstetter, Hans UNSPECIFIED orcid.org/0000-0002-6089-3045 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-587604
DOI:	10.1021/acscatal.1c02057
Journal or Publication Title:	ACS Catal.
Volume:	11
Number:	19
Page Range:	S. 11885 - 11897
Date:	2021
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	2155-5435
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ASPARAGINYL ENDOPEPTIDASE; CIRCULAR PROTEINS; ACTIVATION; ANTIGEN; MACROCYCLIZATION; IDENTIFICATION; SPECIFICITY; MECHANISMS; EXPRESSION; REVEALS Multiple languages Chemistry, Physical Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58760