Importin

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Importin is a type of

cell's cytoplasm to the nucleus. It does so 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

Ran GTP inside the nucleus,[2] with the two importin proteins being recycled to the cytoplasm
for further use.

Discovery

Importin can exist as either a

Ran(TC4). Other key stimulatory factors were also found in the study.[1]

Importin-β, unlike importin-α, has no direct

heterodimer with importin-α in a number of different cases. These included a study led by Michael Rexach[4]
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.

Structure

Importin-α

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 the Importin-β binding (IBB)domain.[6] This is also a site of autoinhibition,[7] and is implicated in the release of cargo once importin-α reaches the nucleus.[8]

Importin-β

Importin-β is the typical structure of a larger

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.[9]

In order to transport cargo into the

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.[10]

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.[11]


Overview of the nuclear protein import cycle.

Cargo transport

Once the cargo protein is bound, importin-β interacts with the

Ran-GTP, ready to be recycled.[11]

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. [7] 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.[11]

Recycling

Finally, in order to return to the

Ran that allows for the unidirectional transport of proteins.[11]

Disease

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

embryogenesis. As a result, a disruption in the expression patterns of importin-α has been shown to cause fertility defects in Drosophila melanogaster.[12]

There have also been studies that link altered importin-α to some cases of

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.[14]

Importin activity is also associated with some

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.[15]
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

References

  1. ^
    S2CID 7539929
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  2. PMID 9759490
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  3. PMID 2004116
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  4. PMID 7622450
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  5. S2CID 6055941
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  6. PMID 21029753
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  7. ^
    PMID 12142282
    .
  8. ^ 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.
    S2CID 16230174
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  9. ^ Lee SJ, Matsuura Y, Liu SM, Stewart M (June 2005). "Structural basis for nuclear import complex dissociation by RanGTP". Nature. 435 (7042): 693–6.
    S2CID 4304731
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  10. S2CID 17495979
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  11. ^
    S2CID 17664108
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  12. ^ Terry LJ, Shows EB, Wente SR (November 2007). "Crossing the nuclear envelope: hierarchical regulation of nucleocytoplasmic transport". Science. 318 (5855): 1412–6.
    S2CID 163986
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  13. ^ 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.
    PMID 10930427
    .
  14. ^ 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.
    PMID 16595783
    .
  15. ^ 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.
    PMID 9384585
    .

External links
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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