The Hypoxic Regulator of Sterol Synthesis Nro1 Is a Nuclear Import Adaptor

SummaryFission yeast protein Sre1, the homolog of the mammalian sterol regulatory element-binding protein (SREBP), is a hypoxic transcription factor required for sterol homeostasis and low-oxygen growth. Nro1 regulates the stability of the N-terminal transcription factor domain of Sre1 (Sre1N) by inhibiting the action of the prolyl 4-hydroxylase-like Ofd1 in an oxygen-dependent manner. The crystal structure of Nro1 determined at 2.2 Å resolution shows an all-α-helical fold that can be divided into two domains: a small N-terminal domain, and a larger C-terminal HEAT-repeat domain. Follow-up studies showed that Nro1 defines a new class of nuclear import adaptor that functions both in Ofd1 nuclear localization and in the oxygen-dependent inhibition of Ofd1 to control the hypoxic response.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (704 K)Download as PowerPoint slideHighlights► The crystal structure shows that Nro1 is a HEAT-repeat motif protein ► Nro1 is the nuclear import adaptor for Ofd1 ► Kap123, a karyopherin-β, mediates the nuclear import of the Nro1-Ofd1 complex ► Inhibition and nuclear localization of Ofd1 by Nro1 map to its N-terminal α helix