Importin α as a central regulator of nucleocytoplasmic transport: Structural basis, isoform diversification, and disease implications.

Eukaryotic cellular homeostasis and function rely on efficient and specific nucleocytoplasmic transport, mediated by nuclear transport machinery. Importin α (Impα), a central adaptor protein in the classical nuclear import pathway, recognizes cargo proteins containing nuclear localization signals (NLSs) and facilitates their translocation into the nucleus. Structurally, this process involves interaction between the importin-β-binding (IBB) domain of Impα and importin β (Impβ), as well as recognition of cargo NLS motifs by major and minor NLS-binding sites formed by armadillo (ARM) repeat domains. The nuclear import function of Impα depends on coordinated spatial configuration and interactions among these conserved structural elements. Comparative structural analyses of Impα from representative organisms-including humans, mice, plants, and fungi-reveal conserved core functional modules with lineage-specific structural variations supporting functional adaptation across taxa. From a pathological perspective, Impα is implicated in multiple human diseases, with dysregulation often rooted in structural and molecular mechanisms. Many viruses exploit the conserved NLS recognition domain of Impα by encoding proteins that mimic host NLSs, hijacking the classical nuclear import pathway to enable viral nuclear entry and immune evasion. In cancer and other chronic diseases, aberrant expression or structural-functional impairment of Impα disrupts nucleocytoplasmic distribution of key signaling molecules and transcriptional regulators, driving disease progression. Given its structural characteristics and role in disease, Impα has emerged as a promising therapeutic target. A systematic understanding of Impα from structure to function and disease relevance provides a framework for developing therapeutic strategies to modulate nucleocytoplasmic transport pathways.