Structural basis for leucine-rich nuclear export signal recognition by CRM1

Area of Science:

• Structural Biology
• Molecular Biology
• Cell Biology

Background:

• CRM1 (exportin 1) is crucial for nuclear export of proteins via leucine-rich nuclear export signals (LR-NES).
• Understanding CRM1-substrate interactions is key to deciphering nuclear transport regulation.

Purpose of the Study:

• To elucidate the structural basis of CRM1 recognition and binding of its cargo, snurportin 1 (SNUPN).
• To characterize the molecular interactions involved in CRM1-mediated nuclear export.

Main Methods:

• X-ray crystallography at 2.9 Å resolution to determine the structure of CRM1 bound to SNUPN.
• Analysis of protein-protein interfaces and interaction motifs.

Main Results:

• The 2.9 Å structure reveals SNUPN binds CRM1 through a bipartite interaction: an N-terminal LR-NES and its nucleotide-binding domain.
• The LR-NES forms an alpha-helical-extended structure fitting into a hydrophobic groove on CRM1.
• A second interaction involves SNUPN's basic surface binding to an acidic patch on CRM1, adjacent to the LR-NES site.

Conclusions:

• Multipartite recognition, involving multiple weak binding sites, may be a common mechanism for CRM1 substrates, enhancing binding affinity.
• This binding strategy provides broad substrate specificity and facilitates rapid evolution in nuclear transport pathways.