Importin α

Last updated

Importin alpha, or karyopherin alpha refers to a class of adaptor proteins that are involved in the import of proteins into the cell nucleus. They are a sub-family of karyopherin proteins. [1]

Contents

Importin α is known to bind to the nuclear localization signal (NLS) sequence of nucleus targeted proteins. [2] After this recognition, importin α links the protein to importin β, which transports the NLS-containing protein across the nuclear envelope to its destination. [3] Because of their complementary functional relationship, importin α and importin β are often referred to as the importin α/β heterodimer, but they are functionally separate, and do not normally exist in conjugation with each other, but only associate for cellular import processes, thus importin α proteins constitute an independent class of adaptor protein.

Structure

Importin α is a small protein consisting of three functionally distinct domains: the IBB domain, ARM domain, and exportin CAS binding domain. [3]

The N-terminal region of the proteins consists of an importin-β-binding, or IBB, domain. This region of the protein is responsible for interaction with importin β. [3] This region has been described as a series of at least 41 essential amino acid residues, specifically positions 10-50 of the protein. Deletion of a single one of these amino acids has been shown to decrease nuclear import activity by around 50%. Larger deletions correlate with even greater losses of function of the ternary import complex made up of importin α, importin β, and the targeted protein. [4]

The majority of the importin α protein is made up of a series of ten tandem armadillo, or ARM, repeats. A centralized ARM domain, consisting of nine of the ARM repeats, is responsible for regulating the NLS binding to directly interact with nucleus targeted proteins. [3] These ARM repeats recognize the basic residues that are characteristic of NLS sequences. NLS sequences can be monopartite (single cluster of basic amino acids) or bipartite (two clusters of basic amino acids with a linker sequence). The ARM domain contains two binding sites within, allowing a single importin α molecule to interact with two monopartite NLS-containing proteins or a single bipartite NLS protein. [5]

The C-terminus domain of importin α, which include the tenth ARM repeat, is responsible for interacting with exportin CAS, another karyopherin protein that functions in recycling importin α from the nucleus back into the cytoplasm of the cell. The association of this exportin CAS binding domain is Ran-GTP dependent, and hydrolysis of GTP leads to dissociation of importin α from the exportin CAS-Ran complex. [3]

NLS binding to the ARM domain, and thereby the formation of the import complex, is regulated by the IBB domain of importin α. The IBB domain of importin α molecules contain many basic amino acid residues, similar to those found in NLS sequences. [4] This similarity in structure leads to the ability of the IBB domain to fold inward and occupy the NLS binding sites when there is not importin β molecule associated with the importin α. This auto-inhibition mechanism prevents importin α from binding NLS containing proteins unless there is already an importin β associated ensuring that binding does not occur before all necessary import machinery is available. [6] Because of this, importin α alone has a fairly low affinity for NLS sequences and a higher NLS affinity is observed when both importin α and importin β are present. [7]

Functions

The primary function of importin α is its role in the nuclear import of proteins containing a NLS sequence. [2] Nuclear import via the Importin α pathway can be summarized by the following six step cycle: [3]

  1. The ARM repeats of free importin α in the cytoplasm bind the NLS of nucleus targeted proteins while the IBB domain simultaneously joins to an importin β protein, forming a ternary complex.
  2. The ternary complex is bound at a docking site on the Nuclear Pore Complex (NPC)
  3. Importin β mediates transport across the nuclear envelope
  4. The ternary complex dissociates due to the binding of importin β to Ran-GTP
  5. Free importin α forms an export complex along with exportin CAS and Ran-GTP and is transported out of the nucleus
  6. GTP is hydrolyzed and the export complex dissociates, releasing free importin α into the cytoplasm

While this nuclear import process does make up the majority of the functional role of importin α proteins, several other important functions have been shown to be mediated by importin αs including gametogenesis, development, heat shock response, protein degradation, and viral pathogen infection. [3] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Gametogenesis has been shown to be greatly influence by importin α proteins in multiple different ways. Animal models using Caenorhabditis elegans, Drosophila melanogaster, and higher order mammal organisms have shown that importin α is abundant in developing gametes, and mutations that cause functional alterations lead can lead to gamete defects and sterility. [3] [8] [10] [12] [13] In bovine models, knockout of importin α encoding genes has been shown to prevent development of fertilized embryos to the blastocyst stage, thus preventing proper embryonic development and leading to death of the organism. [11] Importin α has also been implicated in the development of heat shock response in Drosophila embryos. [9] Additionally, Importin α import has been shown to regulated protease function, including that of Taspase1, a degrader of leukemia proteins. [13]

Taken together, it is clear that importin α proteins are absolutely crucial to proper cellular functioning, and mutations of these proteins can have many disastrous and potentially lethal effects.

Role in viral pathogenicity

Studies have linked importin α with the recognition and import of some viral nucleoproteins, including those of the influenza A virus. [15] It has been discovered that the Influenza A virus accesses this host machinery via a NLS like sequence toward the N-terminus of the viral nucleoprotein that can be recognized by importin α class proteins. This sequence occurs within the first 20 amino acid positions of the viral nucleoprotein and contains clusters of basic amino acids, much like those found in host NLS sequences and the importin α IBB domain. Because of this structural similarity, influenza A viral nucleoprotein is able to be imported into the nucleus of its host and take over replication machinery to proliferate. Simian Immunodeficiency Virus (SIV) is also known to take advantage of the importin α pathway via a NLS like sequence. [16]

Related Research Articles

<span class="mw-page-title-main">Nuclear pore</span>

A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexes (NPCs) in the nuclear envelope of a vertebrate cell, but this number varies depending on cell type and the stage in the life cycle. The human nuclear pore complex (hNPC) is a 110 megadalton (MDa) structure. The proteins that make up the nuclear pore complex are known as nucleoporins; each NPC contains at least 456 individual protein molecules and is composed of 34 distinct nucleoporin proteins. About half of the nucleoporins typically contain solenoid protein domains—either an alpha solenoid or a beta-propeller fold, or in some cases both as separate structural domains. The other half show structural characteristics typical of "natively unfolded" or intrinsically disordered proteins, i.e. they are highly flexible proteins that lack ordered tertiary structure. These disordered proteins are the FG nucleoporins, so called because their amino-acid sequence contains many phenylalanine–glycine repeats.

A nuclear localization signalorsequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different nuclear localized proteins may share the same NLS. An NLS has the opposite function of a nuclear export signal (NES), which targets proteins out of the nucleus.

<span class="mw-page-title-main">STAT protein</span> Family of intracellular transcription factors

Members of the signal transducer and activator of transcription (STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis which enhances the survival of tumors and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.

Karyopherins are proteins involved in transporting molecules between the cytoplasm and the nucleus of a eukaryotic cell. The inside of the nucleus is called the karyoplasm. Generally, karyopherin-mediated transport occurs through nuclear pores which act as a gateway into and out of the nucleus. Most proteins require karyopherins to traverse the nuclear pore.

Importin is a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).

<span class="mw-page-title-main">Armadillo repeat</span>

An armadillo repeat is the name of a characteristic, repetitive amino acid sequence of about 42 residues in length that is found in many proteins. Proteins that contain armadillo repeats typically contain several tandemly repeated copies. Each armadillo repeat is composed of a pair of alpha helices that form a hairpin structure. Multiple copies of the repeat form what is known as an alpha solenoid structure.

<span class="mw-page-title-main">Ran (protein)</span> GTPase functioning in nuclear transport

Ran also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.

Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association with transport factors known as nuclear transport receptors, like karyopherins called importins to enter the nucleus and exportins to exit.

<span class="mw-page-title-main">Nucleoporin</span> Family of proteins that form the nuclear pore complex

Nucleoporins are a family of proteins which are the constituent building blocks of the nuclear pore complex (NPC). The nuclear pore complex is a massive structure embedded in the nuclear envelope at sites where the inner and outer nuclear membranes fuse, forming a gateway that regulates the flow of macromolecules between the cell nucleus and the cytoplasm. Nuclear pores enable the passive and facilitated transport of molecules across the nuclear envelope. Nucleoporins, a family of around 30 proteins, are the main components of the nuclear pore complex in eukaryotic cells. Nucleoporin 62 is the most abundant member of this family. Nucleoporins are able to transport molecules across the nuclear envelope at a very high rate. A single NPC is able to transport 60,000 protein molecules across the nuclear envelope every minute.

<span class="mw-page-title-main">Importin subunit alpha-1</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-1 is a protein that in humans is encoded by the KPNA2 gene.

<span class="mw-page-title-main">KPNB1</span> Protein-coding gene in the species Homo sapiens

Importin subunit beta-1 is a protein that in humans is encoded by the KPNB1 gene.

<span class="mw-page-title-main">Importin subunit alpha-5</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-5 is a protein that in humans is encoded by the KPNA1 gene.

<span class="mw-page-title-main">Importin subunit alpha-4</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-4 also known as karyopherin subunit alpha-3 is a protein that in humans is encoded by the KPNA3 gene.

<span class="mw-page-title-main">Importin subunit alpha-7</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-7 is a protein that in humans is encoded by the KPNA6 gene.

<span class="mw-page-title-main">IPO5</span> Protein-coding gene in the species Homo sapiens

Importin-5 is a protein that in humans is encoded by the IPO5 gene. The protein encoded by this gene is a member of the importin beta family. Structurally, the protein adopts the shape of a right hand solenoid and is composed of 24 HEAT repeats.

<span class="mw-page-title-main">Nucleoporin 153</span> Protein-coding gene in the species Homo sapiens

Nucleoporin 153 (Nup153) is a protein which in humans is encoded by the NUP153 gene. It is an essential component of the basket of nuclear pore complexes (NPCs) in vertebrates, and required for the anchoring of NPCs. It also acts as the docking site of an importing karyopherin. On the cytoplasmic side of the NPC, Nup358 fulfills an analogous role.

<span class="mw-page-title-main">Transportin 1</span> Protein-coding gene in the species Homo sapiens

Transportin-1 is a protein that in humans is encoded by the TNPO1 gene.

<span class="mw-page-title-main">IPO13</span> Protein-coding gene in the species Homo sapiens

Importin-13 is a protein encoded by the IPO13 gene in humans. Importin-13 is a member of the importin-β family of nuclear transport receptors (NTRs) and was first identified as a transport receptor in 2000. According to PSI-blast based secondary structure PREDiction (PSIPRED), importin-13 contains 38 α-helices. Importin-13 accommodates a range of cargoes due to its flexible superhelical structure and a cargo binding and release system that is distinct from other importin-like transport receptors. IPO13 is broadly expressed in a variety of tissues in the human body, including the heart, cornea, fetal lung, brain, endometrial carcinoma, and testes.

A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a protein located in the cytoplasm for import to the nucleus. The NES is recognized and bound by exportins.

<span class="mw-page-title-main">Rev (HIV)</span> HIV-1 regulating protein

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

References

  1. ↑ Köhler, Matthias; Speck, Christian; Christiansen, Marret; Bischoff, F. Ralf; Prehn, Siegfried; Haller, Hermann; Görlich, Dirk; Hartmann, Enno (1 November 1999). "Evidence for Distinct Substrate Specificities of Importin α Family Members in Nuclear Protein Import". Molecular and Cellular Biology. 19 (11): 7782–7791. doi:10.1128/MCB.19.11.7782. ISSN   0270-7306. PMC   84838 . PMID   10523667.
  2. 1 2 Moroianu, J; Blobel, G; Radu, A (14 March 1995). "Previously identified protein of uncertain function is karyopherin alpha and together with karyopherin beta docks import substrate at nuclear pore complexes". Proceedings of the National Academy of Sciences of the United States of America. 92 (6): 2008–2011. Bibcode:1995PNAS...92.2008M. doi: 10.1073/pnas.92.6.2008 . ISSN   0027-8424. PMC   42412 . PMID   7892216.
  3. 1 2 3 4 5 6 7 8 Goldfarb, David S.; Corbett, Anita H.; Mason, D. Adam; Harreman, Michelle T.; Adam, Stephen A. (2004). "Importin α: a multipurpose nuclear-transport receptor". Trends in Cell Biology. 14 (9): 505–514. doi:10.1016/j.tcb.2004.07.016. PMID   15350979.
  4. 1 2 Görlich, D; Henklein, P; Laskey, R A; Hartmann, E (15 April 1996). "A 41 amino acid motif in importin-alpha confers binding to importin-beta and hence transit into the nucleus". The EMBO Journal. 15 (8): 1810–1817. doi:10.1002/j.1460-2075.1996.tb00530.x. ISSN   0261-4189. PMC   450097 . PMID   8617226.
  5. ↑ Lange, Allison; Mills, Ryan E.; Lange, Christopher J.; Stewart, Murray; Devine, Scott E.; Corbett, Anita H. (23 February 2007). "Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin α". Journal of Biological Chemistry. 282 (8): 5101–5105. doi: 10.1074/jbc.R600026200 . ISSN   0021-9258. PMC   4502416 . PMID   17170104.
  6. ↑ Kobe, Bostjan (1 April 1999). "Autoinhibition by an internal nuclear localization signal revealed by the crystal structure of mammalian importin α". Nature Structural & Molecular Biology. 6 (4): 388–397. doi:10.1038/7625. ISSN   1072-8368. PMID   10201409. S2CID   20026752.
  7. ↑ Moroianu, J; Blobel, G; Radu, A (25 June 1996). "The binding site of karyopherin alpha for karyopherin beta overlaps with a nuclear localization sequence". Proceedings of the National Academy of Sciences of the United States of America. 93 (13): 6572–6576. Bibcode:1996PNAS...93.6572M. doi: 10.1073/pnas.93.13.6572 . ISSN   0027-8424. PMC   39066 . PMID   8692858.
  8. 1 2 Giarrè, Marianna; Török, Istvan; Schmitt, Rolf; Gorjánácz, Mátyás; Kiss, István; Mechler, Bernard M. (1 October 2002). "Patterns of importin-α expression during Drosophila spermatogenesis". Journal of Structural Biology. 140 (1–3): 279–290. doi:10.1016/S1047-8477(02)00543-9. PMID   12490175.
  9. 1 2 Fang, Xiang-dong; Chen, Tianxin; Tran, Kim; Parker, Carl S. (1 September 2001). "Developmental regulation of the heat shock response by nuclear transport factor karyopherin-α3". Development. 128 (17): 3349–3358. doi: 10.1242/dev.128.17.3349 . ISSN   0950-1991. PMID   11546751.
  10. 1 2 Geles, K. G.; Adam, S. A. (15 May 2001). "Germline and developmental roles of the nuclear transport factor importin (α)3 in C. elegans". Development. 128 (10): 1817–1830. doi:10.1242/dev.128.10.1817. ISSN   0950-1991. PMID   11311162.
  11. 1 2 Tejomurtula, Jyothsna; Lee, Kyung-Bon; Tripurani, Swamy K.; Smith, George W.; Yao, Jianbo (1 August 2009). "Role of Importin Alpha8, a New Member of the Importin Alpha Family of Nuclear Transport Proteins, in Early Embryonic Development in Cattle". Biology of Reproduction. 81 (2): 333–342. doi: 10.1095/biolreprod.109.077396 . ISSN   0006-3363. PMID   19420384.
  12. 1 2 Yasuhara, Noriko; Yamagishi, Ryosuke; Arai, Yoshiyuki; Mehmood, Rashid; Kimoto, Chihiro; Fujita, Toshiharu; Touma, Kenichi; Kaneko, Azumi; Kamikawa, Yasunao (2013). "Importin Alpha Subtypes Determine Differential Transcription Factor Localization in Embryonic Stem Cells Maintenance". Developmental Cell. 26 (2): 123–135. doi: 10.1016/j.devcel.2013.06.022 . PMID   23906064.
  13. 1 2 3 Hogarth, Cathryn A.; Calanni, Sophina; Jans, David A.; Loveland, Kate L. (1 January 2006). "Importin α mRNAs have distinct expression profiles during spermatogenesis". Developmental Dynamics. 235 (1): 253–262. doi: 10.1002/dvdy.20569 . ISSN   1097-0177. PMID   16261624. S2CID   86703945.
  14. ↑ Bier, Carolin; Knauer, Shirley K.; Docter, Dominic; Schneider, Günter; Krämer, Oliver H.; Stauber, Roland H. (1 June 2011). "The Importin-Alpha/Nucleophosmin Switch Controls Taspase1 Protease Function". Traffic. 12 (6): 703–714. doi: 10.1111/j.1600-0854.2011.01191.x . ISSN   1600-0854. PMID   21418451. S2CID   205841729.
  15. 1 2 Wang, P.; Palese, P.; O'Neill, R. E. (1 March 1997). "The NPI-1/NPI-3 (karyopherin alpha) binding site on the influenza a virus nucleoprotein NP is a nonconventional nuclear localization signal". Journal of Virology. 71 (3): 1850–1856. doi:10.1128/JVI.71.3.1850-1856.1997. ISSN   0022-538X. PMC   191255 . PMID   9032315.
  16. 1 2 Singhal, Prabhat K.; Kumar, P. Rajendra; Rao, Malireddi R. K. Subba; Kyasani, Mahesh; Mahalingam, Sundarasamy (1 January 2006). "Simian Immunodeficiency Virus Vpx Is Imported into the Nucleus via Importin Alpha-Dependent and -Independent Pathways". Journal of Virology. 80 (1): 526–536. doi:10.1128/JVI.80.1.526-536.2006. ISSN   0022-538X. PMC   1317556 . PMID   16352576.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.