Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Nuclear export receptor CRM1 (also known as XPO1) mediates the transport of hundreds of different cargoes from the nucleus to the cytoplasm.
• CRM1 recognizes nuclear export signals (NESs) on its cargo proteins.
• Previous studies demonstrated CRM1's ability to bind NESs in both polypeptide orientations.

Purpose of the Study:

• To elucidate the structural basis for CRM1's recognition of diverse NES sequences.
• To analyze the conformational flexibility of NESs when bound to CRM1.
• To identify conserved interactions that confer specificity to CRM1-NES binding.

Main Methods:

• X-ray crystallography was employed to determine the structures of CRM1 bound to eight additional NESs.
• Structural analysis of all available CRM1-NES complexes was performed.
• Bioinformatic analysis was used to identify conserved features and interactions.

Main Results:

• Eight new crystal structures revealed diverse NES conformations, ranging from loop-like to helical.
• Analysis of all NES structures identified 5-6 distinct backbone conformations.
• A conserved main chain hydrogen bond with CRM1 Lys568 acts as a specificity filter, preventing non-NES peptide binding.
• The flexibility in NES backbone conformation explains the lack of a fixed pattern for hydrophobic anchor residues.

Conclusions:

• CRM1 exhibits remarkable adaptability in binding a wide array of NES sequences due to the conformational plasticity of NESs.
• The invariant Lys568 residue of CRM1 functions as a critical specificity determinant.
• These findings provide a structural explanation for the broad substrate specificity of the nuclear export receptor CRM1.