2014 Group 3 Project

From CellBiology

UNSW ANAT3231 Course Coordinator Dr Mark Hill
2014 Projects: Group 1 | Group 2 | Group 3 | Group 4

Nucleocytoplasmic Transport


Ring-like Nuclear Pores spanning across the Nuclear Envelope.

The nuclear envelope shares an analogous structure to the plasma membrane and other membrane-enclosed organelles. It is a phospholipid bilayer that is composed of two layers, the outer and inner membrane, which act as a barrier for pathogens or other proteins that would disturb gene expression. The outer membrane faces the cytoplasm and is closely associated with the rough endoplasmic reticulum. The inner membrane faces the nucleoplasmic side which supports and interacts with filaments of the nuclear lamina. As the nuclear membrane is only permeable to some small molecules, the nuclear envelope has a special channel that permits different types of molecules to cross the membrane. These pores in the membrane allow for bidirectional transport of large ribosomal subunits, proteins and other large molecules with the help of a transport receptor known as a karyopherin. This channel has its specificities and a particular way of functioning that controls the exchange of macromolecules between the cytoplasm and the nucleoplasm and it is known as the Nuclear Pore Complex (NPC) which is made up of small proteins called nucleoporins. Transport is also facilitated by heterotrimeric G proteins; in particular, Ran which helps accommodate the direction of the molecules. Although the nuclear envelope is an exceptional mediator, there are certain proteins that do not need the help of transport receptors to pass through the nuclear pore complex.

Additional Links

Nuclear Envelope Representation

Nuclear Envelope


Date Significant Discovery
1913 The structure of the nuclear Envelope was first described as a double membrane that encloses the nucleus.[1]
1950 Electron microscopy revealed that the nuclear envelope had two layers,a continuous internal layer and an outer porous layer.[2]
1955 Watson established that the nuclear envelope is closely linked with the endoplasmic reticulum when observing under electron microscopy of interphase cells.[3]
1965 Feldherr discovered that the maximum amount of angstroms to pass through the NPCs was approximately 125 to 145 angstroms in diameter.[4]

1980 The short basic classical-NLS was first discovered as well as their karyopherin-bound structures.[5]
1989 Researcher,Hans Ris was in search for the function and structure of nuclear pore complexes but instead found the specific structures which was termed nucleoporins. Nucleoporins were discovered using high resolution electron microscopy.[6]
1993 Ran GTPase was first discovered and was found to have a strong link to nucleocytoplasmic transport of ran-dependent proteins and transcription factors.[7]
2000 Rout et al provided data to support the brownian virtual gate model as the most preferred model to demonstrate transport across the nuclear membrane for both small and large molecules.[8]


Scaffolding Nup188 structure with ARM and HEAT repeats[9]

Nucleoporins (nups) are the basic building blocks of Nuclear Pore Complexes which span across the Nuclear Envelope allowing for directional transport(active and facilitated). There are different types of nucleoporins that make up the nuclear pore complex, each with their own diverse role. Some nucleoporins are involved in scaffolding and some are involved in forming the octagonal symmetrical hole for both small and large molecules to pass through [8]. The way to identify a nup is it's molecular weight in kDa (kilodaltons), e.g. nup140. By identifying the molecular weight, one is able to tell whether or not that specific nucleoporin is involved in scaffolding or transport[8]. Most nucleoporins contain an N-terminal and C-terminal with Armadillo (ARM) and HEAT Repeats which are helical solenoid protein domains which are commonly found in cytoplasmic proteins with functions in transport[9].

Nucleoporins and Their Localisation Across the NPC[10]
Vertebrate and Yeast Nucleoporins Table[11]
Vertebrate Nucleoporin Homologous Yeast Nucleoporin Localisation Motifs
Nup153b Nup1 (114) nuclear FXFG
Nup62 Nsp1 (87) symmetrical FG, FXFG
Nup50 Nup2 (78) nuclear-biased FXFG
NLP1/hCG1 (45) Nup42 cytoplasmic FG
Nup58, Nup45 Nup49 symmetrical GLFG, FG
Nup35 Nup53 symmetrical
Nup35 Nup59 symmetrical
Nup54 Nup57 symmetrical GLFG, FG
Nup88 Nup82 cytoplasmic
Nup107 Nup84 symmetrical
Nup75/Nup85 Nup 85 symmetrical
Nup93 Nic 96 symmetrical
Nup98 Nup100 cytoplasmic-biased GLFG
Nup98 Nup 116 cytoplasmic-biased FG, GLFG
Nup98 Nup145N (60) nuclear-biased GLFG
Nup160 Nup120 symmetrical
Nup133 Nup133 symmetrical
Nup96 Nup145C (85) symmetrical
Nup155 Nup157 symmetrical
Nup155 Nup 170 symmetrical
Nup214/CAN Nup159 cytoplasmic FG

Phenylalanine and Glycine Rich Nuclear Pores (FG-Nups)

Phenylalanine and Glycine Rich Nuclear Pores (FG-Nups) have repeat amino acid (AA) sequences in 13 out of 30 currently discovered Nucleoporins. These FG-nups contain extensive regions of FG repeats (FG/FXFG/GLFG) spanning from 200 to 700 AA long sequences which is important for selective passage. FG Repeat Motifs are important due to their hydrophobic binding sites attaching to certain cargo transporting receptors (karyopherins/transportins/importins)[12]. The structure of FG-Nups is intrinsically disordered and are always dynamic in vitro, and cannot be fully assessed due to their sheer size and their position within the nuclear membrane[13]. It was revealed that size is a huge factor rather than molecular charge, in determining passive diffusion of small molecules through the Nuclear Pore Complex(NPC).[14]

Molecular Charged GFPs Passing through NPC[14]

For passive diffusion, molecules that are less than 9 nanometers (nm) in diameter and are <40 kDa are able to diffuse through the NPCs[15]. By coating Gold balls with Complex-cargo coating and incubating it in Transport Receptor solution, it is found that large molecules roughly 39nm in diameter are able to enter the karyoplasm through facilitated transport with these Nuclear Localisation Sequences [15]. This also goes hand in hand with the theory that the central axial hole within the NPC is ~410 Angstroms (A) or 41 nm wide in diameter[16].

Nuclear Pore Complex (NPC)

NPC Models

Nuclear Pore Complexes are biologically integral in the export and import of large ribosomal proteins, subunits and various proteins involved in oncogenesis, gene expression and other nuclear activities. NPCs are crucial in transport, as they have to selectively transit ~600,000 different macromolecules every minute in a single eukaryotic cell[17]. For many years, biologists have researched numerous mechanisms as to how macromolecules can be transported in and out of Nucleocytoplasmic barrier. However, difficulties in obtaining a clear and accurate model of the specific transport were faced due to the dynamic arrangement of the disordered FG-Nups and the various interactions that occur within the NPC. Currently, there are four accepted models which aim to account for the selective permeability of the NPC, the interactions of transport receptors with the FG-Nups and the different conduits in the NPC that allow for diffusion and translocation[18].

These models include:

Brownian Virtual Gate Model[8]

1) The Brownian Virtual Gate Model

The virtual gate model implies that the intrinsically disordered FG-Nups behave like ‘repulsive bristles’ which creates an entropic barrier on both ends of the nuclear pore complex.[19] This entropic barrier repels large cargo particles due to the ‘push’ that the FG-Nups provide in keeping the large cargoes away from the central channel. However, this repulsion can be overcome if transport receptors bind to the FG-Nups whereby nuclear pore channels become open and permeable, ultimately allowing large cargos to enter the NPC[20]. According to Rout et al, the most accepted model for nuclear transport is the Brownian virtual gate model.[8]

Selective Phase Model

2) The Selective Phase Model

The selective phase model suggests that the central channel of the NPC is saturated with FG-nups in which the FG repeats are linked together via hydrophobic interactions to form a sieve-like meshwork. This allows only small molecules to pass via passive diffusion therefore restricting the entry of large molecules. When transport factors bind to these FG motifs, it breaks the hydrophobic interactions between the FG-repeats, therefore allowing complete translocation of the macromolecule[18].

Reduction of Dimensionality Model

3) The Reduction of Dimensionality Model

The reduction of dimensionality model suggests that the FG motifs line the internal surface of the NPC which act as binding sites for transport receptors and the cargo they carry on-board.[21] The transport receptors then bind to the FG-repeats and then continuously proceed to the inner surface with a random 2D walk carrying their cargo molecules with them until they enter or exit the nucleus[18].

Forest Model

4) The Forest Model

The forest model proposes that the FG-repeats in the FG-Nups present two different conformations. These FG-Nups are classified into “shrubs” which are said to have a collapsed-coil conformation with cohesive FG domains and low charge, as well as “trees” which present itself as an extended coil with FG domains being non-cohesive and having a high charge.[22] These conformations therefore lead to a forest type structure in the central channel due to the formation of a central and peripheral pathway for the transport of large and small molecules respectively.[23]

Nuclear Transport Receptors

Importin Structure and Binding Complexes

Karyopherins are a family of proteins that have the function of transporting proteins, RNAs and other macromolecules to the nucleus or cytoplasm through the Nuclear Pore Complex (NPC). By binding with nucleoporins, these nucleocytoplasmic transport receptors can travel through the nuclear envelope depending on the type of nuclear transport receptor attached. The family is divided into two groups: importins and exportins. There are more importins than exportins receptors[24]and a limited number of karyopherins altogether. Each one of the karyopherins has multiple cargoes it can transport. It is also understood that distinct associations are formed with different substrates[25]. When it binds to a cargo molecule aiming to take it from the nucleus to the cytoplasm, the transport mediator is called exportins, whereas when it goes the opposite way they are called importins. There are also two bi-directional receptors found so far and one that has not been characterised yet[26]. All the karyopherins have similar molecular weight, which varies from 95 to 145 kDa, and a structure that is very alike[27].The Karyopherin Superfamily of transport receptors are made up of tandem HEAT repeats, usually containing ~18 HEAT repeat motifs in their structure [28]. The HEAT Repeats continuously stack on top of each other and create a superhelical structure made up of three important domains: N-terminal Ran-binding site, nucleoporin-binding site and C-terminal cargo-binding site[29].Within the Nucleoporin structure are repeat FG Domains that have a binding site specific to karyopherins for transport across the nuclear membrane[30]. Additionally, the possible substrate must present a signal that has to be either the Nuclear Localisation Signal (NLS) or the Nuclear Export Signal (NES), in order to go towards the nucleus or cytoplasm respectively. Also the Karyopherins:cargo complex transport is regulated by RanGTP/GDP cycle.[31]

Importins and Binding Sites of Cargo

[[File:NLS of P50.jpg|300px|thumb|right|NLS alignment of p50 peptide with Imp-α Family[32] A Nuclear Localisation Sequence (NLS) is a sequence within a protein that binds specifically to an importin/karyopherin for transport from the cytoplasm to the karyoplasm. The NLS can bind to multiple transport receptors but can have a higher affinity for certain karyopherins. An example would be the N50 peptide extracted from the NLS of NFκB1/p50, and that it can bind to multiple importins but has higher affinity binding to importin α5 (Imp α5)[32]. It is said that importin-α works mostly as an adaptor that can recognise a range of classical NLSs[33] and cannot transport most cargo molecules without attaching to it's counterpart Importin-β[34]. A protein that bears a NLS is recognised by importin-α, the latter which then binds with importin-β and thus form a heterotrimeric complex consisting of Cargo/Importin-α/Importin-β. The importin-β on the complex then interacts with the nucleoporins in the NPC[35] and regulates the affinity of the cargo with the heterotrimer[36]. The transport of Cargo molecules does not need the Importin-α to bind to the cargo molecule and can just be transported by Importin-β by itself[24] by recognising what is known as a "nonclassical" NLS. In this case the binding does not require an adaptor for translocation[37]. In both cases RanGTP binds to importin-β in the nucleus, the substrate is released[38], and the importins returns to the cytoplasm without the cargo[39].


The most studied exportin is Crm1, which is found in yeast cells, and it has only one export cargo which is the importin-alpha[40]. Although Crm1 has low affinity for Ran-GTP and NES, when the three of them are together they form a stable complex[41]that will cross the NPC towards the cytoplasm, where the protein is going to be released[42] as RanGTP is hydrolysed to RanGDP.[43]

List of karyopherins[26]
Mammalian karyopherins S.cerevisiae karyopherins Function Cargo molecules
Importin-β Kap95p They control cell cycle regulation transcription factors Swi4p, Swi6p and Mbp1p.
Importin-4 Kap123p Controls cytoskeletal regulation Nbp1p
Importin-9 Kap114p Kap114p plays a role in nucleosome assembly via its interactions with histones H2A/H2B as well as the histone chaperone Nap1p. Mammalian importin-9 plays a role in the regulation of gene expression. Importin-9 imports actin and Kap114p imports TFIIB.
RanBP5 Pse1p/Kap121p They play a role in importing transcription factors which regulate the mating of haploids Pse1p imports Ste12p and RanBP5 imports newly synthesized polymerase.
Exportin-5 Msn5p/Kap142p Msn5p is involved in the adaptation of cells in various environmental conditions whereas exportin-5 is involved in the export of double-stranded RNA binding domain proteins and double-stranded RNAs cargos. Mammalian exportin-5 exports double-stranded RNAs and proteins whereas S. cerevisiae Msn5p imports and exports cargo proteins such as Far1p and Swi5p. It also exports tRNAs.
Los1p/exportin-t Los1p/exportin-t Mediates the nuclear export of tRNAs tRNA
CAS/CSE1L Cse1p Cse1p Is Involved in Export of Yeast Importin α. importin-α
Importin-13 - Serves to function in Meiosis Imports ubiquitin-conjugating enzyme 9.
CRM1/Exportin-1 KAP124 Mediates intracellular regulation of many cellular processes such as early mammalian embryogenesis Exports leucine-rich nuclear export signals.

On the video below it is clear how these transport receptors work. The first part shows a importin-alpha mediated transport. The blue is the NLS signaling cargo, which goes from cytoplasm to nucleus, where the RanGTP binds to the receptor thus releasing the cargo. The second part, the NES signaling cargo (blue) binds to the exportin and the complex then bind to the RanGTP (red). Once it happens, they cross the NPC and the RanGTP is hydrolysed and the cargo released in the cytoplasm.

transport video

G-Protein Involved in Directional Transport and Cargo Uncoupling of Karyopherin-Cargo Complexes

Ran is a G-Protein that belongs to the Ras superfamily which belongs to another group of hydrolysis enzymes. The key features of G Proteins are their G-Domains in their protein structure which usually are involved with nucleotide exchange, especially the nucleotide Guanine. Ran has a Triphosphate and Diphosphate state known as RanGTP and RanGDP respectively. RanGTP is mostly predominant within the karyoplasm of a cell and is involved in regulation, disassociation and also protein translocation of large cargos. Due to the nature of RanGTP, it forms an association with Impβ1/Impα-mediated nuclear import and/or Impβ1-mediated nuclear import that have passed through the Nuclear Pore Complex from the cytoplasm to the nucleus. RanGTP then binds to these nuclear import proteins and disassociates the cargo from the receptors[44]. The export of large cargoes through Exportin Proteins is analogous in function to its homologous neighbor, Importins. The exportin protein only shows high affinity with the cargo molecule in the presence of RanGTP, which speeds the process of binding to form a trimeric complex which then

RanGTP and RanGDP Dissociating Cargoes [45]

proceeds to interact with the Nucleoporins within the NPC and is released into the cytoplasm of the cell. RanGTP is hydrolysed to RanGDP with the assistance of RAN GTPase activating Protein (ranGAP)and its cofactor Ran-binding protein 1 (ranBP1) which dissociates the Exportin Protein from the cargo in the cytoplasm to perform their respective function[45]. RanGDP is regulated and converted into RanGTP by another protein known as RCC1 or RanGEF, which is localised within the nucleoplasm [46]. This cycling process is know as the RanGTP/GDP cycle.

Within the cell, RanGTP accumulates within the nucleoplasm for complex breakdown of the importin and the cargo, while on the other side of the membrane, RanGDP is predominantly found within the cytoplasm of the cell where it dissociates the large cargos transported out of the nucleus. Weis and Nachury determined that RanGTP also played a role in directionality by inverting the gradient by putting RanGTP in the cytoplasm rather than the karyoplasm [47].It is functionally important that RanGTP is localised within the karyoplasm of the cell, as it is biologically paramount in directionality of macromolecular transport since it disassociates the Importin-Cargo Complex. Within the Nuclear Pore Complex, there were no sightings of ran-binding sites on the nucleoporins except for the nonessential nup2p, further implicating that RanGTP has no social interactions with the Nuclear Pore Complex and is only rather for dissociating the transport receptors from the complex molecule and acting as a transport gradient[8]. In essence this further supports the idea of Brownian diffusion model supported by a selective gating channel.

Nuclear Import and Export with the Assistance and Description of RanGTP and RanGDP Function <mediaplayer>http://www.youtube.com/watch?v=SlLhuVSVlMY</mediaplayer>

IMP and Ran-independent nuclear import pathways

All these proteins listed here have the ability to pass through NPC without the use of a Ran GTP gradient or with the help of an Karyopherin from the Importin Family.


Carrier-independent transport of β-catenin.

β-catenin, also known as Catenin (cadherin-associated protein), beta 1, 88kDa is an essential protein that serves to control the coordination of cell–cell adhesion and gene transcription. It plays a critical role in the WNT signalling pathway, whereby the nuclear accumulation of β-catenin stimulates the signal transduction. [48] It had previously been thought that β-catenin travelled through the Nuclear Pore complex to enter the nucleus via the formation of a complex with the LEF/TCF family, one that doesn't have a NLS sequence. [49]However, experiments have shown that the rapid migration of β-catenin into the nucleus is independent of soluble factors such as the cytosolic extract, Ran or the hydrolysis of ATP/GTP. This revealed that β-catenin can accumulate into the nucleus in a Ran-unassisted manner which is similar to the mechanisms of transport seen in importin α/β and transportin. [50] Both β-Catenin and importin β possess tandem repeating motifs which are called Armadillo and HEAT respectively. These repeats are structurally similar and bind directly to the FXGF-repeats of the Yeast nucleoporins NUP1, suggesting that they travel into the nucleus through the interaction on the same site of the NPC. [51] As such, the transport of the protein β-catenin into the nuclear pore complex is independent of RAN signalling pathways and can freely accumulate into the nucleus for its respective functions.

SMAD transcription factors

The receptor regulated SMADs serve as transcription factors which enable transcription of collagen type I during the fibrogenesis of hepatic stellate cells in the liver and hair morphogenesis in animals.[52] For transcription to occur, these SMAD transcription factors must be activated by cellular receptors and dimerise through phosphorylation by which they can bind to a specific DNA motif as they enter the nucleus. SMAD transcription factors employ two methods to enter the nucleus, one of which uses karyopherins to interact with the nucleoporins, such as the binding of importin-α to importin-β and the subsequent recognition of the NLS motifs labelled on the cargo which allows the importin-β-importin-α-cargo complex to enter the nucleus via the NPC.[53] The other route requires no energy or carrier molecules, but instead uses direct interaction of the SMAD transcription factors to the Nucleoporins. The hydrophobic region in the SMAD MH2 domain binds to the FG-motifs on the specific nucleoporins Nup153 and Nup214.[54] This binding mechanism enables the SMAD transcription factors to sweep its way from the cytoplasm to the nucleus, where they can then bind to DNA motifs to initiate transcription.


ERK2 is the abbreviated term for extracellular signal-regulated kinase 2 and belongs to the family of mitogen-activated protein kinases. It contributes significantly to the regulation of various cellular mechanisms such as the proliferation, differentiation, and survival of cells. [55] The characteristic that makes ERK2 unique to other kinases is its ability to rapidly accumulate in the nucleus without depending on mechanisms that rely on energy and carrier molecules for importation. Experimental data has shown that the transport of ERK2 is a facilitated mechanism that requires the direct binding of ERK2 to the FG-repeats that are bound to their associated nucleoporins.[56] ERK2 is also known to bind to multiple NPC proteins such as Nup214 and Nup153, further supporting the ERK2-FG-nup driven mechanism for transport from the cytoplasm to the nucleus. Furthermore, the type of state that the ERK2 molecule exhibits, greatly affects the mechanism as to how it enters and exits the nucleus. ERK2 in the unphosphorylated state travels to the nucleus by an energy-independent process which is carried out by its direct interaction with nucleoporins.[57] Likewise, small concentrations of phosphorylated ERK2 can be imported and exported from the nucleus via an energy- and carrier-independent process. However, highly concentrated phosphorylated ERK2 undergoes an energy driven process that requires the interaction of CRM-1, which uses karyopherin-β family members such as importin-beta and exportins.[58] As such, the transport of ERK2 in and out of the nucleus can occur via two mechanisms that either requires or doesn’t require energy. Yet, the energy-independent method of transport is more efficient and enables the rapid transport of ERK2 into the nucleus.


Transport of STAT molecules via both carrier-independent(A) and carrier-dependent pathways(B).[59]

The STAT protein, which is also known as signal transducer and activator of transcription, controls various cellular processes including the growth, survival and differentiation of cells. They can also serve to function as transcription factors if they are phosphorylated by Janus kinase (JAK), whereby they can then enter the nucleus to bind to the gamma-activated sites (GAS) of the DNA to promote transcription of cytokine-inducible genes.[60] However, this process requires the use of karyopherins, which specifically uses carrier molecules such as importin-α5 to enter the nucleus.[61] Nevertheless, Stat proteins and transcription factors can enter the nucleus via carrier-independent pathways if the stat protein or transcription factor exists in an unphosphorylated state. The nuclear translocation of Stat1, Stat3, and Stat5 in its unphosphorylated state can occur via the direct binding of the stat protein or transcription factor to the FG-repeats of Nup153 and Nup214.[59] As such, this leads to the rapid transport of the STAT protein or transcription factor making the nucleus completely saturable.

Diseases involved with NPCs

Once the structure of the nuclear pore complex and function is known, it’s possible to analyse the diseases associated with the specific defected nucleoporins that normally span the entire NPC complex. Diseases related to the altered nucleoporins involve various types of cancer, viral infections, neuro-degeneration and cardiovascular diseases. Below is a list of some of the various diseases that can occur via defects associated with the nucleoporins.

Affected Nucleoporin Description
Nup88 This protein belongs to the nucleoporins family and forms a dynamic subcomplex with the oncogenic nucleoporin CAN/Nup214.[62] It acts as a nuclear exporter of activated NF-kappaB transcription factors, ultimately leading to the nuclear accumulation of NF-kappaB.[63] Overexpression of the Nup88 leads to its invasive state in tumour cells. It is commonly found that the overexpression of Nup88 is dominant in breast and colon hepatic cancer as well as many other colorectal cancers.[64] Both diseases can be life threatening if not diagnosed and treated at early stages.
Nup98 The Nup98 protein functions to provide a docking site for the transport of certain substrates. It is associated with the fusion of several genes involving chromosome translocations in acute myelogenous.[65] Since this nucleoporin plays an important role in RNA export from the nucleus,[66] some diseases have been related to the malfunction of Nup98. For instance, myeloid and lymphoid malignancies[67] , a genetic disorder that affects expression of Nup98 gene; and vesicular stomatitis, a virus disease in which the pathogen interacts with this nucleoporin[68] and blocks RNA exportation from nucleus, thus providing a better environment for the virus to replicate. Also, a mutation in the translocation process of Nup98 with HOXA9 is seen in leukemia, whereby this mutation affects the expression of oncogenes and prevents hematopoietic cell differentiation.[69]
Nup62 Nup 62 can be used as an indicator by acting as an autoantigen for Systemic Lupus Erythematosus, an autoimmune disease which often results in inflammation of target organs[70]. Due to Nup62 having a flexible protein FG Repeat Domain compared to other Nucleoporins (e.g. Scaffolding Nups), and that it is a glycoprotein, this might be the cause of why Nup62 has high immunogenicity[71][72]. Nup62 might also be closely associated with billiary cirrhosis by serving as a marker[73], much like Systemic Lupus Erythematosus.
Nup143 and p62 These nucleoporins are related to import of material from cytoplasm to nucleus. Some viruses degradate these proteins and thus attenuate the immune response, achieving a high replication rate.[69]

Future Research

http://www.hindawi.com/journals/mi/2014/476357/ http://www.ncbi.nlm.nih.gov/pubmed/24625024


Amino acid – building blocks of protein.

Angstroms – measure of distance, 10−10 m .

Armadillo (ARM) repeats – are repetitive amino acid sequence which are approximately 40 amino acids long and are found in β-catenin.

FG-Nups - Phenylalanine and Glycine Rich Nuclear Pores.

Glycine – amino acid

G-proteins – proteins with the ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP)

Guanine - nucleotide

HEAT Repeats – are binding domains for Ran, importins and exportins cargo transport proteins.

In vitro – in glass.

Karyopherin – family of proteins involved in the transport of macromolecules across the NPC.

karyoplasm – also known as nucleoplasm.

kDa – kilodaltons, unit of mass.

NES – nuclear export signal.

NLS – nuclear localisation signal.

NPC – nuclear pore complex.

Nucleoporins – proteins that make up the NPC.

Phenylalanine – amino acid

Ran - is a small G-protein roughly around 25 kDa that is essential for the dissociation of transport receptors/proteins or cargo complexes through the NPC.

ranBP1 - Ran-binding protein 1 is a class of proteins regulating the binding and hydrolysis of GTP by Ras-related proteins.

ranGAP - is a protein that carries out the transport of other proteins from the cytosol to the nucleus in eukaryotic cells.

Ras – a family of hydrolytic enzymes.

RCC1 or RanGEF - Regulator of chromosome condensation 1 is a human gene and protein that serves as a guanine nucleotide exchange factor for Ran GTPase.


Molecular Charged GFPs Passing through NPC[14] Brownian Affinity Gate Model[8] RanGTP and RanGDP Dissociating Cargoes [45] Nucleoporins and Their Localisation Across the NPC[10] Transport of STAT molecules via both carrier-independent(A) and carrier-dependent pathways(B).[59]


  1. <pubmed>PMC2829960</pubmed>
  2. <pubmed>14786306</pubmed>
  3. <pubmed>PMC2223813</pubmed>
  4. <pubmed>14283630</pubmed>
  5. <pubmed>20951026</pubmed>
  6. <pubmed>11879632</pubmed>
  7. <pubmed>8276887</pubmed>
  8. 8.0 8.1 8.2 8.3 8.4 8.5 8.6 <pubmed>10684247</pubmed>
  9. 9.0 9.1 <pubmed>23795296</pubmed>
  10. 10.0 10.1 <pubmed>23959328</pubmed>
  11. A. V. Sorokin, E. R. Kim, and L. P. OvchinnikovREVIEW: Nucleocytoplasmic Transport of Proteins Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia URL:[1]
  12. <pubmed>12604785</pubmed>
  13. <pubmed>23238392</pubmed>
  14. 14.0 14.1 14.2 <pubmed>24558427</pubmed>
  15. 15.0 15.1 <pubmed>11854401</pubmed>
  16. <pubmed>1617726</pubmed>
  17. <pubmed>8599106</pubmed>
  18. 18.0 18.1 18.2 <pubmed>21647294</pubmed>
  19. <pubmed>23218007</pubmed>
  20. <pubmed>14624840</pubmed>
  21. <pubmed>21690354</pubmed>
  22. <pubmed>21402022</pubmed>
  23. <pubmed>20647373</pubmed>
  24. 24.0 24.1 <pubmed>15450977</pubmed>
  25. <pubmed>10353244</pubmed>
  26. 26.0 26.1 <pubmed>24766099</pubmed>
  27. <pubmed>14504656</pubmed>
  28. <pubmed> 16567089</pubmed>
  29. <pubmed>21029754</pubmed>
  30. <pubmed>12791264</pubmed>
  31. <pubmed>17287812</pubmed>
  32. 32.0 32.1 24042087</pubmed>
  33. <pubmed>10745017</pubmed>
  34. <pubmed>9640541</pubmed>
  35. <pubmed>9640541</pubmed>
  36. <pubmed>10806202</pubmed>
  37. <pubmed>9640541</pubmed>
  38. <pubmed>8909533</pubmed>
  39. <pubmed>9351834</pubmed>
  40. <pubmed>9774694</pubmed>
  41. <pubmed>10766770</pubmed>
  42. <pubmed>9323134</pubmed>
  43. <pubmed>9428644</pubmed>
  44. <pubmed>15702986</pubmed>
  45. 45.0 45.1 45.2 <pubmed>24733961</pubmed>
  46. <pubmed>1944575</pubmed>
  47. <pubmed>10449743</pubmed>
  48. <pubmed>9501980</pubmed>
  49. <pubmed>9351813</pubmed>
  50. <pubmed>10198061</pubmed>
  51. <pubmed>9391096</pubmed>
  52. <pubmed>16322555</pubmed>
  53. <pubmed>2916443</pubmed>
  54. <pubmed>12191473</pubmed>
  55. <pubmed>14622137</pubmed>
  56. <pubmed>12032311</pubmed>
  57. <pubmed>11546808</pubmed>
  58. <pubmed>16595679</pubmed>
  59. 59.0 59.1 59.2 <pubmed>15210729</pubmed>
  60. <pubmed>15606747</pubmed>
  61. <pubmed>2930068</pubmed>
  62. <pubmed>9049309</pubmed>
  63. <pubmed>19700630</pubmed>
  64. <pubmed>14999780</pubmed>
  65. <pubmed>23246429</pubmed>
  66. <pubmed>9015297</pubmed>
  67. <pubmed>21948299</pubmed>
  68. <pubmed>11106761</pubmed>
  69. 69.0 69.1 <pubmed>12163599</pubmed>
  70. <pubmed>20648220</pubmed>
  71. <pubmed>3313397</pubmed>
  72. <pubmed>17544442</pubmed>
  73. <pubmed>8608894</pubmed>