Nuclear Export Receptor CRM1 Recognizes Nuclear Export Signals with Diverse Conformations




Fung, Ho Yee Joyce

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The Chromosome Region of Maintenance 1 or CRM1 protein facilitates export of hundreds of proteins and RNA molecules from eukaryotic cell nuclei. CRM1 recognizes its protein cargoes by their 8-15 residues-long nuclear export signals or NESs, which bind to a hydrophobic groove in CRM1. NESs are highly variable in sequence and structure. Their sequences are described by multiple sequence patterns of four variably-spaced hydrophobic residues, and three previous structures showed CRM1-bound NESs adopting either helix-strand or mostly extended conformations while the CRM1 groove remains unchanged. The plasticity of CRM1-NES interaction and the repertoire of NES conformations were unclear. Many NES sequences also seem incompatible with the asymmetric and seemingly structurally invariant NES-bound CRM1 groove. I developed a general strategy to crystallize CRM1 bound to NES peptides in order to study how diverse sequences bind CRM1. In the first study, I solved crystal structures of CRM1 bound to NESs with unusual sequences, which bound the CRM1 groove in the opposite orientation (minus) to that of previously studied NESs (plus). Comparison of minus and plus NESs identified structural and sequence determinants for NES orientation. The binding of NESs to CRM1 in both orientations results in a large expansion in NES consensus patterns and therefore a corresponding expansion of potential NESs in the proteome. In the second study, I solved eight additional structures of diverse NESs, which show peptide conformations ranging from mostly loop-like to all-helical NESs, occupying the CRM1 groove to different extents. Comparison of >13 structures show a total of 5-6 different NES conformations where the only conserved structural element is one turn of helix, which has dihedral angles that proceed from helical to β-strand. All NESs also participate in hydrogen bonds with the human CRM1 Lys568 side chain, which functions as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs. We now have comprehensive structural knowledge for NESs of most known patterns. The structural information obtained is now the foundation for a new peptide docking/modeling approach to improve the accuracy of NES prediction.

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