The START domain potentiates HD-ZIPIII transcriptional activity.

The CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIPIII) transcription factors (TFs) were repeatedly deployed over 725 million years of evolution to regulate central developmental innovations. The START domain of this pivotal class of developmental regulators was recognized over 20 years ago, but its putative ligands and functional contributions remain unknown. Here, we demonstrate that the START domain promotes HD-ZIPIII TF homodimerization and increases transcriptional potency. Effects on transcriptional output can be ported onto heterologous TFs, consistent with principles of evolution via domain capture. We also show the START domain binds several species of phospholipids, and that mutations in conserved residues perturbing ligand binding and/or its downstream conformational readout abolish HD-ZIPIII DNA-binding competence. Our data present a model in which the START domain potentiates transcriptional activity and uses ligand-induced conformational change to render HD-ZIPIII dimers competent to bind DNA. These findings resolve a long-standing mystery in plant development and highlight the flexible and diverse regulatory potential coded within this widely distributed evolutionary module.

Diverse regulatory mechanisms of StARkin domains in land plants and mammals.

The StARkin domain (derived from 'kin of steroidogenic acute regulatory protein (StAR)') is an evolutionarily conserved helix-grip-fold structure. StARkin domains possess a deep hydrophobic pocket capable of binding lipophilic ligands such as fatty acids, sterols, and isoprenoids. Dysregulation of StARkin proteins has profound effects on disease and development. In this review, we profile recent mechanistic and evolutionary studies, which highlight the remarkable diversity of regulatory mechanisms employed by the StARkin module. Although primarily focused on land plants, we also discuss select key advances in mammalian StARkin biology. The diversity of perspectives, systems, and approaches described here may be helpful to researchers characterizing poorly understood StARkin proteins.