The intrinsically disordered protein TgIST from Toxoplasma gondii inhibits STAT1 signaling by blocking cofactor recruitment

Zhou Huang, Hejun Liu, Jay Nix, Rui Xu, Catherine R. Knoverek, Gregory R. Bowman, Gaya K. Amarasinghe and L. David Sibley ()
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Zhou Huang: Washington University School of Medicine
Hejun Liu: Washington University School of Medicine
Jay Nix: Lawrence Berkeley National Laboratory
Rui Xu: Washington University School of Medicine
Catherine R. Knoverek: Washington University School of Medicine
Gregory R. Bowman: Washington University School of Medicine
Gaya K. Amarasinghe: Washington University School of Medicine
L. David Sibley: Washington University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Signal transducer and activator of transcription (STAT) proteins communicate from cell-surface receptors to drive transcription of immune response genes. The parasite Toxoplasma gondii blocks STAT1-mediated gene expression by secreting the intrinsically disordered protein TgIST that traffics to the host nucleus, binds phosphorylated STAT1 dimers, and occupies nascent transcription sites that unexpectedly remain silenced. Here we define a core region within internal repeats of TgIST that is necessary and sufficient to block STAT1-mediated gene expression. Cellular, biochemical, mutational, and structural data demonstrate that the repeat region of TgIST adopts a helical conformation upon binding to STAT1 dimers. The binding interface is defined by a groove formed from two loops in the STAT1 SH2 domains that reorient during dimerization. TgIST binding to this newly exposed site at the STAT1 dimer interface alters its conformation and prevents the recruitment of co-transcriptional activators, thus defining the mechanism of blocked transcription.

Date: 2022
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DOI: 10.1038/s41467-022-31720-7

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