Molecular basis for the lack of auto-inhibition of Plasmodium falciparum importin α

Abstract

Importin α is nuclear transport receptor that recognises nuclear localisation sequences (NLS). The protein has two domains: armadillo (ARM) repeats containing NLS-binding sites and the importin β-binding (IBB) domain. The IBB domain mimics an NLS and can bind to the ARM repeats, preventing NLS binding. This phenomenon, called auto-inhibition, is a key regulatory feature for binding and release of NLS-containing cargo by importin α and mutants that lack auto-inhibition show impaired viability in Saccharomyces cerevisiae. The genome of the human malaria parasite, Plasmodium falciparum, contains a single gene for importin α and here we show that the native protein expressed by this gene lacks auto-inhibition, suggesting that P. falciparum parasites possess unconventional mechanisms for regulation of cargo binding and release. Mutation of a single SKR motif (conserved in Plasmodium species) to KRR in P. falciparum importin α restores auto-inhibition. This is the first report of a single-celled eukaryote that has evolved with a single importin α isoform lacking auto-inhibition.