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138  structures 1176  species 9  interactions 13495  sequences 265  architectures

Family: IBN_N (PF03810)

Summary: Importin-beta N-terminal domain

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Importin Edit Wikipedia article

Karyopherin subunit alpha 1
NCBI gene3836
Other data
LocusChr. 3 q21.1
Karyopherin subunit beta 1
NCBI gene3837
Other data
LocusChr. 17 q21.32

Importin is a type of karyopherin[1] that transports protein molecules into the nucleus by binding to specific recognition sequences, called nuclear localization sequences (NLS).

Importin has two subunits, importin α and importin β. Members of the importin-β family can bind and transport cargo by themselves, or can form heterodimers with importin-α. As part of a heterodimer, importin-β mediates interactions with the pore complex, while importin-α acts as an adaptor protein to bind the nuclear localisation signal (NLS) on the cargo. The NLS-Importin α-Importin β trimer dissociates after binding to Ran GTP inside the nucleus,[2] with the two importin proteins being recycled to the cytoplasm for further use.


Importin can exist as either a heterodimer of importin-α/β or as a monomer of Importin-β. Importin-α was first isolated in 1994 by a group including Enno Hartmann, based at the Max Delbrück Center for Molecular Medicine.[1] The process of nuclear protein import had already been characterised in previous reviews,[3] but the key proteins involved had not been elucidated up until that point. A 60kDa cytosolic protein, essential for protein import into the nucleus, and with a 44% sequence identity to SRP1p, was purified from Xenopus eggs. It was cloned, sequenced and expressed in E.coli and in order to completely reconstitute signal dependent transport, had to be combined with Ran(TC4). Other key stimulatory factors were also found in the study.[1]

Importin-β, unlike importin-α, has no direct homologues in yeast, but was purified as a 90-95kDa protein and found to form a heterodimer with importin-α in a number of different cases. These included a study led by Michael Rexach[4] </ref> and further studies by Dirk Görlich.[5] These groups found that importin-α requires another protein, importin-β to function, and that together they form a receptor for nuclear localization signals (NLS), thus allowing transport into the nucleus. Since these initial discoveries in 1994 and 1995, a host of Importin genes, such as IPO4 and IPO7, have been found that facilitate the import of slightly different cargo proteins, due to their differing structure and locality.



A large proportion of the importin-α adaptor protein is made up of several armadillo repeats (ARM) arranged in tandem. These repeats can stack together to form a curved shaped structure, which facilitates binding to the NLS of specific cargo proteins. The major NLS binding site is found towards the N-terminus, with a minor site being found at the C-terminus. As well as the ARM structures, Importin-α also contains a 90 amino acid N-terminal region, responsible for binding to Importin-β, known as IBB (Importin-β binding domain). This is also a site of autoinhibition, and is implicated in the release of cargo once importin-α reaches the nucleus.[6]


Importin-β is the typical structure of a larger superfamily of karyopherins. The basis of their structure is 18-20 tandem repeats of the HEAT motif. Each one of these repeats contains two antiparallel alpha helices linked by a turn, which stack together to form the overall structure of the protein.[7]

In order to transport cargo into the nucleus, importin-β must associate with the nuclear pore complexes. It does this by forming weak, transient bonds with nucleoporins at their various FG (Phe-Gly) motifs. Crystallographic analysis has shown that these motifs bind to importin-β at shallow hydrophobic pockets found on its surface.[8]

Nuclear protein import cycle

The primary function of importin is to mediate the translocation of proteins with nuclear localization signals into the nucleus, through nuclear pore complexes (NPC), in a process known as the nuclear protein import cycle.

Cargo binding

The first step of this cycle is the binding of cargo. Importin can perform this function as a monomeric importin-β protein, but usually requires the presence of importin-α, which acts as an adaptor to cargo proteins (via interactions with the NLS). The NLS is a sequence of basic amino acids that tags the protein as cargo destined for the nucleus. A cargo protein can contain either one or two of these motifs, which will bind to the major and/or minor binding sites on importin-α.[9]

Overview of the nuclear protein import cycle.

Cargo transport

Once the cargo protein is bound, importin-β interacts with the NPC, and the complex diffuses into the nucleus from the cytoplasm. The rate of diffusion depends on both the concentration of importin-α present in the cytoplasm and also the binding affinity of importin-α to the cargo. Once inside the nucleus, the complex interacts with the Ras-family GTPase, Ran-GTP. This leads to the dissociation of the complex by altering the conformation of Importin-β. Importin-β is left bound to Ran-GTP, ready to be recycled.[9]

Cargo release

Now that the importin-α/cargo complex is free of importin-β, the cargo protein can be released into the nucleus. The N-terminal importin-β-binding (IBB) domain of importin-α contains an auto-regulatory region that mimics the NLS motif. The release of importin-β frees this region and allows it to loop back and compete for binding with the cargo protein at the major NLS-binding site. This competition leads to the release of the protein. In some cases, specific release factors such as Nup2 and Nup50 can be employed to help release the cargo as well.[9]


Finally, in order to return to the cytoplasm, importin-α must associate with a Ran-GTP/CAS (nuclear export factor) complex which facilitates its exit from the nucleus. CAS (cellular apoptosis susceptibility protein) is part of the importin-β superfamily of karyopherins and is defined as a nuclear export factor. Importin-β returns to the cytoplasm, still bound to Ran-GTP. Once in the cytoplasm, Ran-GTP is hydrolysed by RanGAP, forming Ran-GDP, and releasing the two importins for further activity. It is this hydrolysis of GTP that provides the energy for the cycle as a whole. In the nucleus, a GEF will charge Ran with a GTP molecule, which is then hydrolysed by a GAP in the cytoplasm, as stated above. It is this activity of Ran that allows for the unidirectional transport of proteins.[9]


There are several disease states and pathologies that are associated with mutations or changes in expression of importin-α and importin-β.

Importins are vital regulatory proteins during the processes of gametogenesis and embryogenesis. As a result, a disruption in the expression patterns of importin-α has been shown to cause fertility defects in Drosophila melanogaster.[10]

There have also been studies that link altered importin-α to some cases of cancer. Breast cancer studies have implicated a truncated form of importin-α in which the NLS binding domain is missing.[11] In addition, importin-α has been shown to transport the tumour suppressor gene, BRCA1 (breast cancer type 1 susceptibility protein), into the nucleus. The overexpression of importin-α has also been linked with poor survival rates seen in certain melanoma patients.[12]

Importin activity is also associated with some viral pathologies. For instance, in the infection pathway of the Ebola virus, a key step is the inhibition of the nuclear import of PY-STAT1. This is achieved by the virus sequestering importin-α in the cytoplasm, meaning it can no longer bind its cargo at the NLS.[13] As a result, importin cannot function and the cargo protein stays in the cytoplasm.

Types of cargo

Many different cargo proteins can be transported into the nucleus by importin. Often, different proteins will require different combinations of α and β in order to translocate. Some examples of different cargo are listed below.

Cargo Import Receptor
SV40 Importin-β and importin-α
Nucleoplasmin Importin-β and importin-α
STAT1 Importin-β and NPI-1 (type of importin-α)
TFIIA Importin-α not required
U1A Importin-α not required

Human importin genes

Although importin-α and importin-β are used to describe importin as a whole, they actually represent larger families of proteins that share a similar structure and function. Various different genes have been identified for both α and β, with some of them listed below. Note that often karyopherin and importin are used interchangeably.

See also


  1. ^ a b c Görlich D, Prehn S, Laskey RA, Hartmann E (December 1994). "Isolation of a protein that is essential for the first step of nuclear protein import". Cell. 79 (5): 767–78. doi:10.1016/0092-8674(94)90067-1. PMID 8001116.
  2. ^ Mattaj IW, Englmeier L (1998). "Nucleocytoplasmic transport: the soluble phase". Annual Review of Biochemistry. 67: 265–306. doi:10.1146/annurev.biochem.67.1.265. PMID 9759490.
  3. ^ Garcia-Bustos J, Heitman J, Hall MN (March 1991). "Nuclear protein localization". Biochim. Biophys. Acta. 1071 (1): 83–101. doi:10.1016/0304-4157(91)90013-m. PMID 2004116.
  4. ^ Enenkel C, Blobel G, Rexach M (July 1995). "Identification of a yeast karyopherin heterodimer that targets import substrate to mammalian nuclear pore complexes". J. Biol. Chem. 270 (28): 16499–502. doi:10.1074/jbc.270.28.16499. PMID 7622450.
  5. ^ Görlich D, Kostka S, Kraft R, Dingwall C, Laskey RA, Hartmann E, Prehn S (April 1995). "Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope". Current Biology. 5 (4): 383–92. doi:10.1016/s0960-9822(95)00079-0. PMID 7627554.
  6. ^ Conti E, Uy M, Leighton L, Blobel G, Kuriyan J (July 1998). "Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin alpha". Cell. 94 (2): 193–204. doi:10.1016/s0092-8674(00)81419-1. PMID 9695948.
  7. ^ Lee SJ, Matsuura Y, Liu SM, Stewart M (June 2005). "Structural basis for nuclear import complex dissociation by RanGTP". Nature. 435 (7042): 693–6. doi:10.1038/nature03578. PMID 15864302.
  8. ^ Bayliss R, Littlewood T, Stewart M (July 2000). "Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking". Cell. 102 (1): 99–108. doi:10.1016/s0092-8674(00)00014-3. PMID 10929717.
  9. ^ a b c d Weis K (February 2003). "Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle". Cell. 112 (4): 441–51. doi:10.1016/s0092-8674(03)00082-5. PMID 12600309.
  10. ^ Terry LJ, Shows EB, Wente SR (November 2007). "Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport". Science. 318 (5855): 1412–6. doi:10.1126/science.1142204. PMID 18048681.
  11. ^ Kim IS, Kim DH, Han SM, Chin MU, Nam HJ, Cho HP, Choi SY, Song BJ, Kim ER, Bae YS, Moon YH (July 2000). "Truncated form of importin alpha identified in breast cancer cell inhibits nuclear import of p53". The Journal of Biological Chemistry. 275 (30): 23139–45. doi:10.1074/jbc.M909256199. PMID 10930427.
  12. ^ Winnepenninckx V, Lazar V, Michiels S, Dessen P, Stas M, Alonso SR, Avril MF, Ortiz Romero PL, Robert T, Balacescu O, Eggermont AM, Lenoir G, Sarasin A, Tursz T, van den Oord JJ, Spatz A (April 2006). "Gene expression profiling of primary cutaneous melanoma and clinical outcome". Journal of the National Cancer Institute. 98 (7): 472–82. doi:10.1093/jnci/djj103. PMID 16595783.
  13. ^ Sekimoto T, Imamoto N, Nakajima K, Hirano T, Yoneda Y (December 1997). "Extracellular signal-dependent nuclear import of Stat1 is mediated by nuclear pore-targeting complex formation with NPI-1, but not Rch1". The EMBO Journal. 16 (23): 7067–77. doi:10.1093/emboj/16.23.7067. PMC 1170309. PMID 9384585.

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This article incorporates text from the public domain Pfam and InterPro: IPR002652
This article incorporates text from the public domain Pfam and InterPro: IPR001494

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Importin-beta N-terminal domain Provide feedback

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InterPro entry IPR001494

This entry represents the N-terminal domain of importin-beta (also known as karyopherins-beta) that is important for the binding of the Ran GTPase protein [PUBMED:10367892].

Members of the importin-beta (karyopherin-beta) family can bind and transport cargo by themselves, or can form heterodimers with importin-alpha. As part of a heterodimer, importin-beta mediates interactions with the pore complex, while importin-alpha acts as an adaptor protein to bind the nuclear localisation signal (NLS) on the cargo through the classical NLS import of proteins. Importin-beta is a helicoidal molecule constructed from 19 HEAT repeats. Many nuclear pore proteins contain FG sequence repeats that can bind to HEAT repeats within importins [PUBMED:12372823, PUBMED:17161424], which is important for importin-beta mediated transport.

Ran GTPase helps to control the unidirectional transfer of cargo. The cytoplasm contains primarily RanGDP and the nucleus RanGTP through the actions of RanGAP and RanGEF, respectively. In the nucleus, RanGTP binds to importin-beta within the importin/cargo complex, causing a conformational change in importin-beta that releases it from importin-alpha-bound cargo. As a result, the N-terminal auto-inhibitory region on importin-alpha is free to loop back and bind to the major NLS-binding site, causing the cargo to be released [PUBMED:17170104]. There are additional release factors as well.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan TPR (CL0020), which has the following description:

Tetratricopeptide-like repeats are found in a numerous and diverse proteins involved in such functions as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.

The clan contains the following 157 members:

Adaptin_N Alkyl_sulf_dimr ANAPC3 ANAPC5 ANAPC8 API5 Arm Arm_2 Arm_3 Atx10homo_assoc B56 BAF250_C BTAD CAS_CSE1 ChAPs CHIP_TPR_N CID CLASP_N Clathrin Clathrin-link Clathrin_H_link Clathrin_propel Cnd1 Cnd3 Coatomer_E Cohesin_HEAT Cohesin_load ComR_TPR COPI_C CPL CRM1_C Cse1 CTK3 DHR-2 DNA_alkylation Drf_FH3 Drf_GBD DUF1822 DUF2019 DUF2225 DUF3385 DUF3458_C DUF3808 DUF3856 DUF4042 DUF5691 DUF924 EST1 EST1_DNA_bind FAT Fis1_TPR_C Fis1_TPR_N Foie-gras_1 GUN4_N HAT HEAT HEAT_2 HEAT_EZ HEAT_PBS HemY_N HrpB1_HrpK HSM3_N IBB IBN_N IFRD Importin_rep_3 Importin_rep_6 KAP Leuk-A4-hydro_C LRV LRV_FeS MA3 MIF4G MIF4G_like MIF4G_like_2 MMS19_C Mo25 MRP-S27 Mtf2 NARP1 Neurochondrin Nipped-B_C Nro1 NSF Paf67 ParcG PC_rep PHAT PI3Ka PknG_TPR PPP5 PPR PPR_1 PPR_2 PPR_3 PPR_long PPTA Proteasom_PSMB PUF Rab5-bind Rapsyn_N RIX1 RNPP_C RPM2 RPN7 Sel1 SHNi-TPR SNAP SPO22 SRP_TPR_like ST7 Suf SusD-like SusD-like_2 SusD-like_3 SusD_RagB SYCP2_ARLD TAF6_C TAL_effector TAtT Tcf25 TIP120 TOM20_plant TPR_1 TPR_10 TPR_11 TPR_12 TPR_14 TPR_15 TPR_16 TPR_17 TPR_18 TPR_19 TPR_2 TPR_20 TPR_21 TPR_3 TPR_4 TPR_5 TPR_6 TPR_7 TPR_8 TPR_9 TPR_MalT UNC45-central Upf2 V-ATPase_H_C V-ATPase_H_N Vac14_Fab1_bd Vitellogenin_N Vps39_1 W2 Wzy_C_2 Xpo1 YcaO_C YfiO Zmiz1_N


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Seed source: PROSITE
Previous IDs: IBN_NT;
Type: Family
Sequence Ontology: SO:0100021
Author: Griffiths-Jones SR
Number in seed: 52
Number in full: 13495
Average length of the domain: 72.30 aa
Average identity of full alignment: 20 %
Average coverage of the sequence by the domain: 7.45 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 20.9 20.9
Noise cut-off 20.8 20.8
Model length: 74
Family (HMM) version: 20
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Archea Archea Eukaryota Eukaryota
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There are 9 interactions for this family. More...

Cse1 Ras Xpo1 IBB CAS_CSE1 CRM1_C Parathyroid UQ_con Ras


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the IBN_N domain has been found. There are 138 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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