Mechanistic Insights from Structural Analyses of Ran-GTPase-Driven Nuclear Export of Proteins and RNAs

• Published in: Journal of molecular biology Vol. 428; no. 10; pp. 2025 - 2039
• Main Author: Matsuura, Yoshiyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 22.05.2016
• Subjects: Active Transport, Cell Nucleus - physiology; exportin; Humans; Karyopherins - metabolism; nuclear export signal; Nuclear Pore - metabolism; Nuclear Pore - physiology; nuclear pore complex; Nuclear Pore Complex Proteins - metabolism; Nuclear Proteins - metabolism; nucleoporin; Ran; ran GTP-Binding Protein - metabolism; NPC; NLS; MD; nucleoporin; Nup; nuclear pore complex; nuclear export signal; exportin; NES; NTR; Ran
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2015.09.025

Understanding how macromolecules are rapidly exchanged between the nucleus and the cytoplasm through nuclear pore complexes is a fundamental problem in biology. Exportins are Ran-GTPase-dependent nuclear transport factors that belong to the karyopherin-β family and mediate nuclear export of a plethora of proteins and RNAs, except for bulk mRNA nuclear export. Exportins bind cargo macromolecules in a Ran-GTP-dependent manner in the nucleus, forming exportin-cargo-Ran-GTP complexes (nuclear export complexes). Transient weak interactions between exportins and nucleoporins containing characteristic FG (phenylalanine-glycine) repeat motifs facilitate nuclear pore complex passage of nuclear export complexes. In the cytoplasm, nuclear export complexes are disassembled, thereby releasing the cargo. GTP hydrolysis by Ran promoted in the cytoplasm makes the disassembly reaction virtually irreversible and provides thermodynamic driving force for the overall export reaction. In the past decade, X-ray crystallography of some of the exportins in various functional states coupled with functional analyses, single-particle electron microscopy, molecular dynamics simulations, and small-angle solution X-ray scattering has provided rich insights into the mechanism of cargo binding and release and also begins to elucidate how exportins interact with the FG repeat motifs. The knowledge gained from structural analyses of nuclear export is being translated into development of clinically useful inhibitors of nuclear export to treat human diseases such as cancer and influenza. [Display omitted] •Exportins are Ran-GTPase-dependent nuclear export factors for proteins and RNAs.•Structures of exportins in various functional states have been determined.•Conformational changes in exportins couple cargo binding to Ran-GTP binding.•RanBPs can accelerate assembly/disassembly of nuclear export complexes.•Inhibitors of nuclear export are being developed and may be clinically useful.