Universität zu Köln

Pao, Kuan-Chuan, Wood, Nicola T., Knebel, Axel, Rafie, Karim, Stanley, Mathew, Mabbitt, Peter D., Sundaramoorthy, Ramasubramanian, Hofmann, Kay ORCID: 0000-0002-2289-9083, van Aalten, Daan M. F. and Virdee, Satpal ORCID: 0000-0002-7052-9802 (2018). Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity. Nature, 556 (7701). S. 381 - 406. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Ubiquitination is initiated by transfer of ubiquitin (Ub) from a ubiquitin-activating enzyme (E1) to a ubiquitin-conjugating enzyme (E2), producing a covalently linked intermediate (E2-Ub)(1). Ubiquitin ligases (E3s) of the 'really interesting new gene' (RING) class recruit E2-Ub via their RING domain and then mediate direct transfer of ubiquitin to substrates(2). By contrast, 'homologous to E6-AP carboxy terminus' (HECT) E3 ligases undergo a catalytic cysteine-dependent transthiolation reaction with E2-Ub, forming a covalent E3-Ub intermediate(3,4). Additionally, RING-between-RING (RBR) E3 ligases have a canonical RING domain that is linked to an ancillary domain. This ancillary domain contains a catalytic cysteine that enables a hybrid RING-HECT mechanism(5). Ubiquitination is typically considered a post-translational modification of lysine residues, as there are no known human E3 ligases with non-lysine activity. Here we perform activity-based protein profiling of HECT or RBR-like E3 ligases and identify the neuron-associated E3 ligase MYCBP2 (also known as PHR1) as the apparent single member of a class of RING-linked E3 ligase with esterification activity and intrinsic selectivity for threonine over serine. MYCBP2 contains two essential catalytic cysteine residues that relay ubiquitin to its substrate via thioester intermediates. Crystallographic characterization of this class of E3 ligase, which we designate RING-Cys-relay (RCR), provides insights into its mechanism and threonine selectivity. These findings implicate non-lysine ubiquitination in cellular regulation of higher eukaryotes and suggest that E3 enzymes have an unappreciated mechanistic diversity.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pao, Kuan-Chuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Wood, Nicola T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knebel, Axel UNSPECIFIED UNSPECIFIED UNSPECIFIED Rafie, Karim UNSPECIFIED UNSPECIFIED UNSPECIFIED Stanley, Mathew UNSPECIFIED UNSPECIFIED UNSPECIFIED Mabbitt, Peter D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sundaramoorthy, Ramasubramanian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Kay UNSPECIFIED orcid.org/0000-0002-2289-9083 UNSPECIFIED van Aalten, Daan M. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Virdee, Satpal UNSPECIFIED orcid.org/0000-0002-7052-9802 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-189180
DOI:	10.1038/s41586-018-0026-1
Journal or Publication Title:	Nature
Volume:	556
Number:	7701
Page Range:	S. 381 - 406
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LINEAR UBIQUITIN CHAINS; ACTIVITY-BASED PROBES; ACTIVATING ENZYMES; COMPLEX REVEALS; MECHANISM; DOMAIN; CONJUGATION; DEGENERATION; INSIGHTS; PATHWAY Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18918