Structural basis for importin alpha 3 specificity of W proteins in Hendra and Nipah viruses

Smith KM1, Tsimbalyuk S1, Edwards MR1, Cross EM1, Batra J2, Soares da Costa TP3, Aragão D4, Basler CF2 and Forwood JK1

  1. School of Biomedical Sciences, Charles Sturt University.
  2. Institute for Biomedical Sciences, Georgia State University.
  3. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University.
  4. 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.