Diversification of importin-α isoforms in cellular trafficking and disease states

The human genome encodes seven isoforms of importin a which are grouped into three subfamilies known as alpha 1, alpha 2 and alpha 3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-beta-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-alpha isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-alpha isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin a into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin alpha is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases.