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

被引:21
|
作者
Gronholm, Juha [1 ]
Vanhatupa, Sari [1 ]
Ungureanu, Daniela [1 ]
Valiaho, Jouni [1 ]
Laitinen, Tuomo [3 ]
Valjakka, Jarkko [1 ]
Silvennoinen, Olli [1 ,2 ]
机构
[1] Univ Tampere, Inst Biomed Technol, FIN-33014 Tampere, Finland
[2] Tampere Univ Hosp, Dept Internal Med, FIN-33521 Tampere, Finland
[3] Univ Eastern Finland, Sch Pharm, Fac Hlth Sci, FIN-70211 Kuopio, Finland
来源
BMC BIOCHEMISTRY | 2012年 / 13卷
基金
英国医学研究理事会;
关键词
Signal transduction; Transcription factors; Sumoylation; Signal transducers and activators of transcription (STATs); Interferon; IFN-GAMMA; TRANSCRIPTION STAT; SUMO-1; CONJUGATION; CRYSTAL-STRUCTURE; GENE ACTIVATION; PROTEIN; UBIQUITIN; CELLS; PIAS1; PHOSPHORYLATION;
D O I
10.1186/1471-2091-13-20
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: STAT1 is an essential transcription factor for interferon-Upsilon-mediated gene responses. A distinct sumoylation consensus site (psi KxE) (IKTE705)-I-702 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-Upsilon-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.
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页数:12
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