Importins (Karyopherin); How proteins are transferred from cytoplasm to the nucleus of a cell

Karyopherins are a group of proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm (nucleoplasm). Generally, karyopherin mediated transport occurs through the nuclear pore, which acts as a gateway into and out of the nucleus. Most proteins require karyopherins to traverse the nuclear pore.
Karyopherins can act as Importins (helping proteins get into the nucleus) or Exportins (helping proteins get out of the nucleus). They belong to Nuclear Pore Complex Family in the Transporter Classification Database (TCDB). The energy for transport is derived from the Ran gradient.
IMPORTINS
Importin is a type of protein that moves other protein molecules into the nucleus by binding to a specific recognition sequence, called the Nuclear Localization Signal (NLS) [This signal consists of one or more short sequences of positively charged lysine or arginine exposed on the protein surface].
Importin has two subunits, importin-α and importin-β. Members of the importin-β family can bind and transport cargo by themselves [HEAT repeats] or can form heterodimers with importin-α. As part of a heterodimer, importin-β mediates interactions with the nuclear pore complex, while importin-α acts as an adaptor protein to bind the NLS on the cargo through the classical NLS import of proteins.
Proteins can contain one (monopartite) or two (bipartite) NLS motifs. Importin-α contains an N-terminal Importin-β Binding Domain (IBB, 90 amino acid) that contains an auto-regulatory region.
Importin-α contains several Armadillo (ARM) repeats [repetitive amino acid sequence of about 40 residues in length], which forms a curving structure with two NLS-binding sites within a shallow groove: the major and minor NLS-binding sites. The major NLS-binding site is close to the N-terminus of importin-α, and binds monopartite, as well as one motif of bipartite NLS cargo. The minor NLS-binding site is closer to the C-terminus of importin-α, and binds the second motif of bipartite NLS cargo.
Importin-β is a helicoidal molecule constructed from 19 HEAT repeats [HEAT repeat is a protein domain. HEAT containing proteins include the Ran-GTP binding importin and exportin cargo transport proteins. A signature motif of the HEAT repeats is the presence of conserved Aspartic Acid and Arginine residues at positions 19 and 25, respectively. Many nuclear pore proteins contain FG sequence [Phenylalanine, Glycine] that can bind to HEAT repeats within importins, which is important for importin-β mediated transport
Transportation needs to be unidirectional to be effective. This is achieved through the compartmentalization of Ran [a small 25kDa protein], which acts to control the binding and release of cargo.
Ran can exist as RanGTP in the nucleus because of Ran Guanine Nucleotide Exchange Factor (RanGEF) and RanGDP, in the cytoplasm, because of Ran GTPase Activating Protein (RanGAP)
Importins release cargo in the presence of RanGTP while Exportins bind cargo in its presence. Therefore, the predominance of RanGTP within the nucleus and RanGDP within the cytoplasm helps to ensure that importins release their cargo within the nucleus upon RanGTP binding, and exportins release their cargo in the cytoplasm upon hydrolysis of RanGTP to GDP.
In the nucleus, RanGTP binds to importin-β within the importin-beta/importin-alpha/cargo trimeric complex, causing a conformational change in importin-β that releases it from importin-α-bound cargo. The N-terminal importin-β-binding (IBB) domain of importin-α contains an auto-regulatory region that mimics the NLS motif. This auto-inhibitory region folds over and competes for binding with cargo at the major NLS-binding site of importin-alpha. Then the Cellular Apoptosis Susceptibility protein (CAS), an exportin, which in the nucleus is bound to RanGTP, displaces Importin-α from the cargo.
The resulting complex of importin-α and CAS-Ran-GTP then translocate to the cytoplasm, where a protein called Ran Binding Protein (RanBP) separates Ran-GTP from importin. The separation allows access to GAP that binds Ran-GTP and induces the hydrolysis of GTP to GDP. 
In an action that prevents the depletion of Ran from the nucleus, the Ran-GDP formed in the cytoplasm is transported back to the nucleus by its own import receptor, known as NTF2. In the nucleus, Ran-GDP is converted back to Ran-GTP by Ran-GEF (Guanine nucleotide exchange factor) for another round of action.