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Open Access Highly Accessed Research article

Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1

Juha Grönholm1, Sari Vanhatupa1, Daniela Ungureanu1, Jouni Väliaho1, Tuomo Laitinen2, Jarkko Valjakka1 and Olli Silvennoinen13*

Author affiliations

1 Institute of Biomedical Technology, University of Tampere, Biokatu 8, Tampere, FIN-33014, Finland

2 Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland, Kuopio, FIN-70211, Finland

3 Department of Internal Medicine, Tampere University Hospital, Tampere, FIN-33521, Finland

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Citation and License

BMC Biochemistry 2012, 13:20  doi:10.1186/1471-2091-13-20

Published: 8 October 2012

Abstract

Background

STAT1 is an essential transcription factor for interferon-γ-mediated gene responses. A distinct sumoylation consensus site (ψKxE) 702IKTE705 is localized in the C-terminal region of STAT1, where Lys703 is a target for PIAS-induced SUMO modification. Several studies indicate that sumoylation has an inhibitory role on STAT1-mediated gene expression but the molecular mechanisms are not fully understood.

Results

Here, we have performed a structural and functional analysis of sumoylation in STAT1. We show that deconjugation of SUMO by SENP1 enhances the transcriptional activity of STAT1, confirming a negative regulatory effect of sumoylation on STAT1 activity. Inspection of molecular model indicated that consensus site is well exposed to SUMO-conjugation in STAT1 homodimer and that the conjugated SUMO moiety is directed towards DNA, thus able to form a sterical hindrance affecting promoter binding of dimeric STAT1. In addition, oligoprecipitation experiments indicated that sumoylation deficient STAT1 E705Q mutant has higher DNA-binding activity on STAT1 responsive gene promoters than wild-type STAT1. Furthermore, sumoylation deficient STAT1 E705Q mutant displayed enhanced histone H4 acetylation on interferon-γ-responsive promoter compared to wild-type STAT1.

Conclusions

Our results suggest that sumoylation participates in regulation of STAT1 responses by modulating DNA-binding properties of STAT1.

Keywords:
Signal transduction; Transcription factors; Sumoylation; Signal transducers and activators of transcription (STATs); Interferon