Consequences of the disease-related L78R mutation for dimerization and activity of STAT3

Journal of Cell Science (Impact Factor: 5.43). 02/2014; 127(9). DOI: 10.1242/jcs.137422
Source: PubMed


STAT3 (signal transducer and activator of transcription 3) is a transcription factor centrally involved in diverse processes including hematopoiesis, immunity and cancer progression. In response to cytokine stimulation STAT3 is activated through phosphorylation of a single tyrosine residue. The phosphorylated STAT3 dimers are stabilized by intermolecular SH2 domain/phosphotyrosine interactions. These activated dimers accumulate in the nucleus and bind to specific DNA sequences resulting in target gene expression. We analysed and compared the structural organizations of the unphosphorylated latent and phosphorylated activated STAT3 dimers using Förster resonance energy transfer (FRET) in fixed and living cells. The latent dimers are stabilized by homotypic interactions between the N-terminal domains. A somatic mutation (L78R) found in inflammatory hepatocellular adenomas (IHCA) which is located in the N-terminal domain of STAT3 disturbs latent dimer formation. Applying intramolecular FRET we verify a functional role of the SH2 domain in latent dimer formation suggesting the parallel orientation of the protomers in the latent STAT3 dimer similar to activated STAT3 dimers but in contrast to the latent dimers of STAT1 and STAT5. Our findings reveal unique structural characteristics of STAT3 within the STAT family and contribute to the understanding of the L78R mutation found in IHCA.

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Available from: Tamás Domoszlai, May 07, 2014
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    • "It was indicated that any deviation of the wild type properties caused by amino acid mutations, enhanced or reduced affinity for example, possesses high risk of developing a disease. Experimentally it was shown that diseasecausing amino acid mutations alter macromolecular interactions (Domoszlai, et al., 2014; Patel, et al., 2011; Placone, et al., 2014; Placone and Hristova, 2012; Wu, et al., 2010; Yang, et al., 2013; Zhang, et al., 2011). Computational studies indicated that amino acid mutations alter binding affinity of proteins and make the electrostatic component of the binding energy less favorable (Nishi, et al., 2013; Teng, et al., 2009). "
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