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. 2010 Dec 23:8:32.
doi: 10.1186/1478-811X-8-32.

Phosphorylation meets nuclear import: a review

Jonathan D Nardozzi  1 , Kaylen Lott, Gino Cingolani
Affiliations

Phosphorylation meets nuclear import: a review (VSports app下载)

V体育安卓版 - Jonathan D Nardozzi et al. Cell Commun Signal. .

Abstract

Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, has been shown to have opposite and often contradictory effects on the ability of cargos to be transported across the nuclear envelope. Without a clear connection between attachment of a phosphate moiety and biological response, it is difficult to fully understand and predict how phosphorylation regulates nucleocytoplasmic trafficking VSports手机版. In this review, we will recapitulate clue findings in the field and provide some general rules on how reversible phosphorylation can affect the nuclear-cytoplasmic localization of substrates. This is only now beginning to emerge as a key regulatory step in biology. .

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Figures

Figure 1
Figure 1
Amino acid sequence of several known nuclear targeting sequences. (A) Classical Nuclear Localization Signals. Nuclear import signals of cargos (B) up-regulated and (C) down-regulated by phosphorylation. Colored in blue are basic amino acids within the import signal, usually critical for recognition by karyopherins. In red are sites of phosphorylation that have been shown to modulate nuclear import.
Figure 2
Figure 2
Diversification of the human nuclear import adaptor importin α. (A) A phylogenetic tree showing the evolutionary divergence of the six different human importin α isoforms. The branch lengths are proportional to the predicted evolutionary time between sequences. Three subfamilies of importin α (shaded in green, yellow and magenta) are identified. Both sequence alignment and phylogenetic tree were generated using the program ClustalW [164]. Ribbon diagram of the mammalian importin α1 (B) (pdb 1EJL) and importin α5 (C) (pdb 2JDQ) (in green and violet, respectively). Both structures consist of 10 tandemly repeated Armadillo repeats (ARM), each formed by three α-helices. Significant differences can be seen between importin α1 and α5 C-terminal ARM-10, which is partially extended in α5 [20]. Both crystal structures in panel (B-C) lack the N-terminal Importin β binding (IBB) domain, which promotes binding to the receptor importin β.
Figure 3
Figure 3
Schematic representation of four distinct mechanisms by which phosphorylation can up-regulate importin β1-dependent nuclear import. (A) Phosphorylation within the NLS of EBNA-1 enhances the binding affinity for importin α5. (B) Phosphorylation of the HBV core antigen causes a conformational change that positions the NLS on the exterior of the capsid, and hence promotes its nuclear import. (C) Phosphorylation of serines upstream of the NLS of SV40 large T-antigen enhances nuclear import likely by enhancing the cargo recognition by importin α1. (D) Phosphorylation of STAT1 at Tyr701 induces a conformational rearrangement that exposes a non-classical dsNLS that is bound specifically and with high affinity by importin α5. In all diagrams, import cargos and importin β1 are colored in cyan and blue, respectively while importin α1 is in green and α5 in violet. The NLS is depicted as a yellow flag and the phosphorylation site, or the kinase responsible for phosphorylation, is in red.
Figure 4
Figure 4
Schematic representation of two phosphorylation-activated transport signals that confer nuclear import independent of importin β1. (A) ERK1/2 (cyan) is sequestered in the cytoplasm by anchoring proteins (shown in grey). Upon phosphorylation at its TEY site, ERK1/2 undergoes a conformational change, causing it to dissociate from the anchoring proteins. This allows MEK access to the NTS which it phosphorylates. Upon NTS phosphorylation, ERK1/2 is recognized and imported into the nucleus by importin β7 (yellow). (B) The SR protein ASF/SF2 (cyan) is phosphorylated at Arg-Ser (RS) dipeptide repeats that function as an NLS for the import receptor importin β2 (also known as transportin), shown in purple.
Figure 5
Figure 5
Structural model of the Vaccinia virus phosphatase, VH1 (pdb 3CM3) in the act of dephosphorylating activated STAT1 (pdb 1BF5). Surface representation of the dimeric phosphatase VH1 modeled in the act of dephosphorylating phosphorylated STAT1 core (in gray and orange, respectively). Ribbon diagram of VH1 and phosphorylated STAT1 are overlaid to their surface. The two active sites within VH1 are spaced 39Å apart. STAT1 flexible moiety connecting phosphorylated Tyr701 to the SH3 domains is modeled as a black dashed line; the two phosphorylated Tyr701 (shown in red) are modeled inside each of VH1 active sites. It is intriguing to speculate that VH1 specificity for activated STAT1 may be mediated by a dimeric quaternary structure. Accordingly, VH1 positions two active sites in the correct three-dimensional complementarity to recognize and dephosphorylate activated STAT1.
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