Structural basis for importin alpha 3 specificity of W proteins in Hendra and Nipah viruses
- School of Biomedical Sciences, Charles Sturt University.
- Institute for Biomedical Sciences, Georgia State University.
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University.
- Australian Synchrotron, Australian Nuclear Science and Technology Organisation.
Seven human isoforms of importin α mediate nuclear import of cargo in a tissue- and isoform-specific manner. Understanding how nuclear import adaptors differentially interact with cargo harbouring the same NLS remains poorly understood since the NLS recognition region is highly conserved. Here, we provide a structural basis for the nuclear import specificity of W proteins in Hendra virus (HeV) and Nipah virus (NiV). We determine the structural interfaces of these cargo and importin α1 and α3, identifying a 2.4-fold more extensive interface and >50-fold binding affinity for importin α3. Through the design of importin α1 and α3 chimeric and mutant proteins, together with structures of cargo-free importin α1 and α3 isoforms, we establish that the molecular basis of specificity resides in the differential positioning of the armadillo-repeats 7 and 8. Overall, our study provides mechanistic insights into a range of important nucleocytoplasmic transport processes reliant on isoform adaptor specificity.