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Molecular and Cellular Biology, February 2006, p. 955-964, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.955-964.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inhibition of DNA Binding by Differential Sumoylation of Heat Shock Factors

Julius Anckar,^1,2, Ville Hietakangas,^1,2,, Konstantin Denessiouk,³ Dennis J. Thiele,⁴ Mark S. Johnson,³ and Lea Sistonen^1,2*

Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, Turku, Finland,¹ Department of Biology, Åbo Akademi University, Turku, Finland,² Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland,³ Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710⁴

Received 2 September 2005/ Returned for modification 7 October 2005/ Accepted 1 November 2005

Covalent modification of proteins by the small ubiquitin-related modifier SUMO regulates diverse biological functions. Sumoylation usually requires a consensus tetrapeptide, through which the binding of the SUMO-conjugating enzyme Ubc9 to the target protein is directed. However, additional specificity determinants are in many cases required. To gain insights into SUMO substrate selection, we have utilized the differential sumoylation of highly similar loop structures within the DNA-binding domains of heat shock transcription factor 1 (HSF1) and HSF2. Site-specific mutagenesis in combination with molecular modeling revealed that the sumoylation specificity is determined by several amino acids near the consensus site, which are likely to present the SUMO consensus motif to Ubc9. Importantly, we also demonstrate that sumoylation of the HSF2 loop impedes HSF2 DNA-binding activity, without affecting its oligomerization. Hence, SUMO modification of the HSF2 loop contributes to HSF-specific regulation of DNA binding and broadens the concept of sumoylation in the negative regulation of gene expression.

These authors contributed equally to this work.

Present address: EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

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