Nuclear import by karyopherin-βs: recognition and inhibition

Abstract

Proteins in the karyopherin-β family mediate the majority of macromolecular transport between the nucleus and the cytoplasm. Eleven of the 19 known human karyopherin-βs and 10 of the 14S. cerevisiae karyopherin-βs mediate nuclear import through recognition of nuclear localization signals or NLSs in their cargos. This receptor-mediated process is essential to cellular viability as proteins are translated in the cytoplasm but many have functional roles in the nucleus. Many known karyopherin-β-cargo interactions were discovered through studies of the individual cargos rather than the karyopherins, and this information is thus widely scattered in the literature. We consolidate information about cargos that are directly recognized by import-karyopherin-βs and review common characteristics or lack thereof among cargos of different import pathways. Knowledge of karyopherin-β-cargo interactions is also critical for the development of nuclear import inhibitors and the understanding of their mechanisms of inhibition. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.

Fig. 1

The Kapβ family of nuclear transport factors. Schematic of all known human and S. cerevisiae Kapβs divided into evolutionary-derived subfamilies [6,7].

Fig. 2

Structures of Kapβ2 bound to PY-NLSs. (A) Structure of Kapβ2 (red) bound to the PY-NLS of hnRNP A1 (green); PDB 2H4M [18]. (B) PY-NLSs of hnRNP A1 (green) and hnRNP M (magenta) upon superposition of the Kapβ2s. Epitopes 1 (N-terminal hydrophobic/basic motifs), 2 and 3 (C-terminal Rx_(2–5)PY motif) structurally converge and are separated by structurally diverse linkers. (C) Sequences of the PY-NLSs in (B) and the consensus sequences.

Fig. 3

Structure of Importin-13 bound to import cargo Y14•Mago. Importin-13 binds the entire Y14•Mago heterodimer. Importin-13 is in pink, Y14 is green and Mago is in cyan. PDB ID 2X1G [151].