The short linker domain (LD) is crucial for providing structural support during activation and DNA binding, and also serves as a contact point during the formation of transcriptional complexes. Many of these conform to the so-called gamma-activated sequence (GAS), a palindromic TTCN 3-4GAA motif present within the promoter region of STAT-responsive target genes. ![]() The DNA-binding domain (DBD) possess an immunoglobin-like structure that mediates recognition and binding to specific DNA target sequences. This domain is also implicated in nuclear translocation via a nuclear localization signal (NLS) motif that interacts with importin proteins to facilitate nuclear entry. ![]() Coiled-coil domainĬontaining several alpha-helices in a ropelike structure, the coiled-coil domain (CCD) facilitates binding to other transcription factors and co-activators such as p48/Interferon regulatory factor 9 (IRF9) and N-Myc and STAT interactor (Nmi), but also to co-repressors such as Silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT)/nuclear receptor co-repressor (N-CoR). It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.Ĭonsisting of multiple alpha-helices that form a hook-like structure, the N-terminal domain (NTD) mediates interactions between STAT molecules that facilitate dimerization even in the absence of phosphorylation. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. However, growing evidence has challenged this paradigm and identified alternate ‘non-canonical’ functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. In this ‘canonical’ paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. ![]() Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function.
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