CRM1

CRM1, also called exportin 1, is a nuclear export receptor of the karyopherin-β family. In humans it is encoded by the XPO1 gene and is a highly conserved mediator of transport from the nucleus to the cytoplasm for proteins that contain a leucine-rich nuclear export signal (NES). CRM1 operates within the RanGTP-dependent export pathway and is essential for the proper localization and regulation of numerous cellular proteins.

In the nucleus, CRM1 binds to NES-containing cargo in a complex with RanGTP. This trimeric complex is transported through the nuclear pore complex to the cytoplasm, where GTP hydrolysis releases the cargo after cargo-CRM1 dissociates in the RanGDP-rich cytoplasmic environment. The directionality of transport is driven by the RanGTP gradient across the nuclear envelope. CRM1 exports a broad range of substrates, including transcription factors, cell cycle regulators, and components involved in ribosome biogenesis; many pathways rely on regulated CRM1-mediated export for proper activity and cellular response.

CRM1 is an HEAT-repeat–containing protein with a structure that forms a flexible, elongated superhelix. This architecture supports cargo binding via the NES recognition groove and undergoes conformational changes coupled to RanGTP binding and hydrolysis, enabling cargo loading and release.

Inhibitors and clinical relevance: CRM1 inhibitors have been investigated as anti-cancer agents. Leptomycin B is a potent natural product that covalently blocks CRM1 by modifying a cysteine in the cargo-binding groove, while a class of selective inhibitors of nuclear export (SINE) compounds, such as selinexor, covalently modify Cys528 in CRM1 to block export. These agents can induce nuclear retention of tumor suppressors and pro-apoptotic signals, showing activity in various cancer types, though they may cause cytopenias and other adverse effects.