Functional Significance of Intrinsically Disordered Conformations in Activation Domains of the Transcription Factors

摘要

In spite of well established fact that gene regulation by the transcription factors (TFs) involves the regulated assembly of multi-protein complexes on enhancers and promoters, scientific community is still actively searching for answers to questions pertaining to the mechanisms that govern this complex process. In this context the structural determinant of activation domains (ADs) of TFs, which provide a basic platform for the assembly of other coregulatory proteins (critical in gene regulation), is of immense importance. It has become quite clear that many TFs possess AD(s), which exist in an intrinsically disordered (ID) conformation. In recent years, it has been shown that significant biological functions are associated with ID states of proteins. Among others, the flexibility of intrinsic disorder in ADs facilitates post-translational modifications, adoption of different conformations with various binding partner proteins, which in turn may lead to its diverse role in gene regulation by the TFs. Thus, proper understanding of ID AD regions in the action of signaling molecules may lead to a new approach for drug discovery, targeted at the assembly of multi-protein complexes involving TFs. This article reviews the available understanding of disorder-order transition in the gene regulation by the TFs, and provides future perspectives for the utilization of this knowledge for novel approaches to drug discovery.