Insight into the molecular recognition mechanism of the coactivator NCoA1 by STAT6

Abstract

Crucial for immune and anti-inflammatory cellular responses, signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 and -13 -induced tyrosine phosphorylation by direct interaction with coactivators. The interaction of STAT6 with nuclear coactivator 1 (NCoA1) is mediated by a short region of the STAT6 transactivation domain that includes the motif LXXLL and interacts with the PAS-B domain of NCoA1. Despite the availability of an X-ray structure of the PAS-B domain/ Leu⁷⁹⁴-Gly⁸¹⁴-STAT6 complex, the mechanistic details of this interaction are still poorly understood. Here, we determine the structure of the NCoA1^257-385/STAT6^783-814 complex using Nuclear Magnetic Resonance (NMR) and X-ray crystallography. The STAT6^783-814 peptide binds with additional N-terminal amino acids to NCoA1^257-385, compared to the STAT6^794-814 peptide, explaining its higher affinity. Secondary and tertiary structures existing in the free peptide are more highly populated in the complex, suggesting binding by conformational selection.