Traditionally, specific DNA recognition is thought to rely on static contacts with the bases or phosphates. Recent results, however, indicate that residues far outside the binding context can crucially influence selectivity or binding affinity via transient, dynamic interactions with the DNA binding interface. These regions usually do not adopt a well-defined structure, even when bound to DNA, and thus form a fuzzy complex. Here, we propose the existence of a dynamic DNA readout mechanism, wherein distant segments modulate conformational preferences, flexibility or spacing of the DNA binding motifs or serve as competitive partners. Despite their low sequence similarity, these intrinsically disordered regions are often conserved at the structural level, and exploited for regulation of the transcription machinery via protein-protein interactions, post-translational modifications or alternative splicing.
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