NDLI: Site-specific inhibition of the small ubiquitin-like modifier (SUMO)-conjugating enzyme Ubc9 selectively impairs SUMO chain formation

Content Provider	Journal of Biological Chemistry (JBC)
Author	Wiechmann, Svenja Gärtner, Anne Kniss, Andreas Stengl, Andreas Behrends, Christian Rogov, Vladimir V. Rodriguez, Manuel S. Dötsch, Volker Müller, Stefan Ernst, Andreas
Abstract	Posttranslational modifications by small ubiquitin-like modifiers (SUMOs) regulate many cellular processes, including genome integrity, gene expression, and ribosome biogenesis. The E2-conjugating enzyme Ubc9 catalyzes the conjugation of SUMOs to ϵ-amino groups of lysine residues in target proteins. Attachment of SUMO moieties to internal lysines in Ubc9 itself can further lead to the formation of polymeric SUMO chains. Mono- and poly-SUMOylations of target proteins provide docking sites for distinct adapter and effector proteins important for regulating discrete SUMO-regulated pathways. However, molecular tools to dissect pathways depending on either mono- or poly-SUMOylation are largely missing. Using a protein-engineering approach, we generated high-affinity SUMO2 variants by phage display that bind the back side binding site of Ubc9 and function as SUMO-based Ubc9 inhibitors (SUBINs). Importantly, we found that distinct SUBINs primarily inhibit poly-SUMO chain formation, whereas mono-SUMOylation was not impaired. Proof-of-principle experiments demonstrated that in a cellular context, SUBINs largely prevent heat shock-triggered poly-SUMOylation. Moreover, SUBINs abrogated arsenic-induced degradation of promyelocytic leukemia protein. We propose that the availability of the new chain-selective SUMO inhibitors reported here will enable a thorough investigation of poly-SUMO-mediated cellular processes, such as DNA damage responses and cell cycle progression.
Related Links	http://www.jbc.org/content/292/37/15340.abstract
Ending Page	15351
Starting Page	15340
Page Count	12
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	37
Volume Number	292
DOI	10.1074/jbc.M117.794255
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2017-09-15
Access Restriction	Open
Subject Keyword	Enzyme inhibitor Nuclear magnetic resonance (NMR) Phage display Protein engineering Small ubiquitin-like modifier (SUMO) Sumoylation UBC9 PML Heat shock Enzymology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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