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Review
. 2010 Dec;20(6):782-90.
doi: 10.1016/j.sbi.2010.09.008. Epub 2010 Oct 13.

Recognition of nuclear targeting signals by Karyopherin-β proteins

Darui Xu  1 , Alicia Farmer, Yuh Min Chook
Affiliations
Review

Recognition of nuclear targeting signals by Karyopherin-β proteins

Darui Xu et al. Curr Opin Struct Biol. 2010 Dec.

Abstract

The Karyopherin-β family of nuclear transport factors mediates the majority of nucleocytoplasmic transport. Although each of the 19 Karyopherin-βs transports unique sets of cargos, only three classes of nuclear localization and export signals, or NLSs and NESs, have been characterized. The short basic classical-NLS was first discovered in the 1980s and their karyopherin-bound structures were first reported more than 10 years ago. More recently, structural and biophysical studies of Karyopherin-β2-cargo complexes led to definition of the complex and diverse PY-NLS. Structural knowledge of the leucine-rich NES is finally available more than 10 years after the discovery of its recognition by the exportin CRM1. We review recent findings relating to how these three classes of nuclear targeting signals are recognized by their Karyopherin-β nuclear transport factors.

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Figures

Figure 1
Figure 1
Classical-NLS recognition by Impα/β. (a) Impβ (pink) binds to the IBB domain of Impα (blue ribbon); PDB ID 1QGK. Monopartite (1EJL) or bipartite (1EJY) classical-NLSs (green) bind to the Impα ARM domain (surface representation in blue). Full length Impα is autoinhibited. An NLS-like N-terminal segment (blue sticks) occupies the major NLS binding site on the ARM domain (blue surface) and prohibits binding of exogeneous NLS; PDB ID 1IAL. A dashed blue line represents the unstructured polypeptide chain that connects the Impα ARM domain to its IBB domain. (b) Interactions between the SV40 T antigen NLS (green) and the major binding site of Impα (grey; PDB ID 1BK6). Conserved tryptophan-asparagine pairs and acidic residues in Impα are colored yellow and magenta, respectively.
Figure 2
Figure 2
The Kapβ2 nuclear import pathway. (a) Crystal structure of Kapβ2 (pink) bound to the PY-NLS of hnRNP A1 (green; also known as the M9 sequence); PDB ID 2H4M. The internal loop in HEAT repeat 8 is mostly disordered and colored yellow. (b) Crystal structure of Kapβ2 (pink) bound to Ran•GppNHp (grey surface); PDB ID 1QBK. When Ran is bound, the H8 loop (yellow) is mostly ordered and binds to the PY-NLS binding site. (c) Structures of PY-NLSs from hnRNPs A1 (green; 2H4M), M (yellow-green; 2OT8), D (blue; 2Z5N) and mRNA export factor TAP/NXF1 (orange; 2Z5K) upon superposition of Kapβ2s. All four peptides spatially converge at epitopes 1, 2 and 3, which are connected by structurally variable linkers. PY-NLS sequences are shown in the box, with residues in epitope 1 shown in yellow (hydrophobic motif) and blue (basic motif) and conserved residues in epitopes 2 and 3 shown in red.
Figure 3
Figure 3
Structures of CRM1 complexes. The structure of CRM1 (pink, surface representation) bound with cargo SNUPN (light blue ribbon) with (a, PDB ID 3GJX) and without (b, PDB ID 3GB8) RanGTP (grey). (c) The structure of CRM1 (pink) bound with RanGTP (grey) and RanBP1 (green; PDB ID 3M1I). (d) The leucine-rich NES of SNUPN (light blue ribbon) bound to the hydrophobic groove of CRM1 (pink). The helices of HEAT repeats 11 and 12 are shown as ribbons and sidechains that line the hydrophobic groove are shown. (e) Rearrangement of the hydrophobic groove in the CRM1-RanGTP-RanBP1 complex. Helices of HEAT repeats 11 and 12 are shown as in (d). Helix movement resulted in narrower or ‘closed’ hydrophobic groove, which is incompatible with NES binding.
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