The First 3D Structure of a Full Length Hox Protein and Evidence for a Conformational Change

Abstract

Hox proteins are an important class of transcription factors that regulate development of region-specific features in bilaterian animals via binding and regulation of target genes. These proteins contain a conserved DNA binding homeodomain (HD), generally near their C-terminus. Despite the large degree of HD conservation between members of the Hox family, each of these proteins oversee unique and specific functions in vivo. The observed discrepancy between specificity of function and similarity in DNA binding has been termed the Hox paradox, and as of yet has no concrete explanation. This work investigates the possibility that proteins modulate DNA binding via intramolecular interactions between N-terminal intrinsically disordered regions (IDRs) and the HD. Here we show via negative stain transmission electron microscopy evidence that the Hox protein Ultrabithorax (Ubx) exists in multiple conformations. In these structures, the arrangement of the HD relative to the N-terminal disordered domains varies, and thus conformation may modulate HD-DNA binding. Because the N-terminus of Hox proteins is less conserved than the HD, it’s possible that these disorder-HD interactions are different in each member of the Hox family, providing a mechanism by which these proteins can uniquely diversify their DNA binding.