STAT1:DNA sequence-dependent binding modulation by phosphorylation, protein:protein interactions and small-molecule inhibition.

Abstract:

:The DNA-binding specificity and affinity of the dimeric human transcription factor (TF) STAT1, were assessed by total internal reflectance fluorescence protein-binding microarrays (TIRF-PBM) to evaluate the effects of protein phosphorylation, higher-order polymerization and small-molecule inhibition. Active, phosphorylated STAT1 showed binding preferences consistent with prior characterization, whereas unphosphorylated STAT1 showed a weak-binding preference for one-half of the GAS consensus site, consistent with recent models of STAT1 structure and function in response to phosphorylation. This altered-binding preference was further tested by use of the inhibitor LLL3, which we show to disrupt STAT1 binding in a sequence-dependent fashion. To determine if this sequence-dependence is specific to STAT1 and not a general feature of human TF biology, the TF Myc/Max was analysed and tested with the inhibitor Mycro3. Myc/Max inhibition by Mycro3 is sequence independent, suggesting that the sequence-dependent inhibition of STAT1 may be specific to this system and a useful target for future inhibitor design.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Bonham AJ,Wenta N,Osslund LM,Prussin AJ 2nd,Vinkemeier U,Reich NO

doi

10.1093/nar/gks1085

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

754-63

issue

2

eissn

0305-1048

issn

1362-4962

pii

gks1085

journal_volume

41

pub_type

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