Journal article

Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting

Kate M Smith, Veronica Di Antonio, Luca Bellucci, David R Thomas, Fabiana Caporuscio, Francesco Ciccarese, Hanieh Ghassabian, Kylie M Wagstaff, Jade K Forwood, David A Jans, Giorgio Palu, Gualtiero Alvisi



Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40..

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University of Melbourne Researchers


Awarded by Ministero dell'Istruzione, dell'Universita e della Ricerca MURST

Awarded by Australian Research Council

Awarded by National Health and Medical Research Council

Awarded by National Breast Cancer Foundation

Funding Acknowledgements

We thank Fatma Hamna, Andrea Contarini, Enrico Lavezzo and Martina Timmoneri (University of Padua) for skilled technical assistance and helpful discussions, and the beamline scientists and staff of the Australian Synchrotron. This work was supported by the Ministero dell'Istruzione, dell'Universita e della Ricerca MURST EX60% (grant 60A07-1024/15 to G.A). We acknowledge the additional financial support of the Australian Research Council (future fellowship FT120100242 to JKF), the National Health and Medical Research Council (Senior Principal Research Fellowship APP1002486/APP1103050 to DAJ), and the National Breast Cancer Foundation (fellowship CDA-17-007 to KMW).