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

 
: Wiechmann, S.; Gärtner, A.; Kniss, A.; Stengl, A.; Behrends, C.; Rogov, V.V.; Rodriguez, M.S.; Dötsch, V.; Müller, S.; Ernst, A.

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The Journal of biological chemistry 292 (2017), Nr.37, S.15340-15351
ISSN: 0021-9258
ISSN: 1083-351X
Englisch
Zeitschriftenaufsatz
Fraunhofer IME ()

Abstract
Posttranslational modifications by small ubiquitin-like modifiers (SUMOs) regulate many cellular processes, including genome integrity, gene expression, and ribosome biogen-esis. The E2-conjugating enzyme Ubc9 catalyzes the conjugation of SUMOs to -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 forma tion, 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.

: http://publica.fraunhofer.de/dokumente/N-470869.html