Quan Y et al. (2008), Evolutionary and transcriptional analysis of ka...

XB-ART-38116

Mol Cell Proteomics 2008 Jul 01;77:1254-69. doi: 10.1074/mcp.M700511-MCP200.

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Evolutionary and transcriptional analysis of karyopherin beta superfamily proteins.

Quan Y , Ji ZL , Wang X , Tartakoff AM , Tao T .

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In eukaryotes, karyopherin beta superfamily proteins mediate nucleocytoplasmic transport of macromolecules. We investigated the evolutionary and transcriptional patterns of these proteins using bioinformatics approaches. No obvious homologs were found in prokaryotes, but an extensive set of beta-karyopherin proteins was found in yeast. Among 14 beta-karyopherins of Saccharomyces cerevisiae, eight corresponded to their human orthologs directly without diversification, two were lost, and the remaining four proteins exhibited gene duplications by different mechanisms. We also identified beta-karyopherin orthologs in Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, Xenopus tropicalis, Gallus gallus, and Mus musculus. beta-Karyopherins were ubiquitously but nonuniformly expressed in distinct cells and tissues. In yeast and mice, the titer of some beta-karyopherin transcripts appeared to be regulated both during the cell cycle and during development. Further virtual analysis of promoter binding elements suggested that the transcription factors SP1, NRF-2, HEN-1, RREB-1, and nuclear factor Y regulate expression of most beta-karyopherin genes. These findings emphasize new mechanisms in functional diversification of beta-karyopherins and regulation of nucleocytoplasmic transport.

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Species referenced: Xenopus tropicalis
Genes referenced: creb1 cse1l hlf hltf ids ipo11 ipo13 ipo4 ipo5 ipo7 ipo8 ipo9 kpnb1 mag sox13 tnpo1 tnpo2 tnpo3 vdr xpo1 xpo4 xpo5 xpo6 xpo7 xpot

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	Fig. 1. Phylogenetic trees constructed on the full-length protein sequences of karyopherin β superfamily members in eight organisms using the neighbor-joining methods provided by the software MEGA4 under the Poisson correction amino acid substitution model with uniform rates among sites. Bootstrap values calculated by MEGA4 are beside their nodes. The β-karyopherins are arranged into 14 trees as shown. Yeast β-karyopherin genes are marked with solid circles. The names of species are abbreviated as follows: Hs, H. sapiens; Mm, M. musculus; Gg, G. gallus; Xt, X. tropicalis; Dr, D. rerio; Dm, D. melanogaster; Ce, C. elegans; and Sc, S. cerevisiae.
	Fig. 2. Comparison of the IBN_N domain (Pfam PF03810) in human β-karyopherins. Multiple sequence alignment of the IBN_N domain residues was performed using MUSCLE3.6 and refined manually on the basis of a reference alignment (importin-β N-terminal domain profile, PROSITE PS50166) and the secondary structure of human KPNB1 (Protein Data Bank 1QGR) ( 79 ). The numbers under “Start site” are positions of the first residues of IBN_N domain in each protein; numbers under “Length” are the number of residues in the IBN_N domain in each protein. A conservation estimate for each position in the alignment is plotted under the alignment. Highly conserved positions in the alignment will get a high score (the peaks), whereas low conservation or exceptional residues at a partially conserved position will lower the score (the valleys). The “:” character indicates that one of the “strong” groups of amino acids is fully conserved, whereas “.” indicates that one of the “weaker” groups of amino acids is conserved as described in ClustalX. Consensus secondary structure predicted using the software JPred ( 80 ) is given above the alignment. Note the conservation of the IBN_N domain in β-karyopherin pairs IPO7-IPO8, IPO13-TNPO3, RANBP5-RANBP6, TNPO1-TNPO2, and XPO7-RANBP17. Sequences were shadedbased on the alignment consensas, which was calculated automatically by the ClustalX program.
	Fig. 3. Comparison of the IBN_N domain (Pfam PF03810) in KPNB1 orthologs.Hs, H. sapiens; Mm, M. musculus; Gg, G. gallus; Xt, X. tropicalis; Dr, D. rerio; Dm, D. melanogaster; Ce, C. elegans; Sc, S. cerevisiae. The sequences were aligned using MUSCLE3.6, and the definitions of the symbols are described in Fig. 2 . “*” indicates positions that are fully conserved. RanGTP binding sites for yeast Kap95p as described previously ( 81 ) are labeled with arrows. Note the conservation of the IBN_N domain through different organisms especially after D. rerio.
	Fig. 4. The exon arrangements of 20 human β-karyopherin genes. The transcript IDs in Ensembl are ENST00000261412, ENST00000356861, ENST00000379719, ENST00000256079, ENST00000252512, ENST00000377354, ENST00000265388, ENST00000372343, ENST00000290158, ENST00000354464, ENST00000361565, ENST00000389352, ENST00000389538, ENST00000255305, ENST00000265351, ENST00000304658, ENST00000389161, ENST00000262982, ENST00000357602, and ENST00000259569, respectively. The shaded blocks are translated regions, whereas the transparent blocks are non-translated regions. The numbers under the blocks are the length of the exon (in bp), and the numbers in parenthesis indicate the length of translated regions when an exon contains a non-translated region. Note the similarity between TNPO1-TPNP2, IPO7-IPO8, and XPO7-RANBP17. RANBP6 has only one exon and is thought to originate from RANBP5 through retroposition.
	Fig. 5. The exon arrangements of RANBP5 and RANBP6 in different organisms, including H. sapiens (Hs), M. musculus (Mm), G. gallus (Gg), X. tropicalis (Xt), D. rerio (Dr), D. melanogaster (Dm), C. elegans (Ce), and S. cerevisiae (Sc). The transcript IDs of these β-karyopherin genes in Ensembl or GenBank are ENST00000357602, ENSMUST00000032898, XM_416978.2, ENSXETT00000050713, XM_692846.2, CG1059-RA, and C53D5.6 YMR308C for RANBP5 and ENST00000361966 and ENSMUST00000046742 for RANBP6. The shaded blocks are translated regions, whereas the transparent blocks are non-translated regions. The numbers under the blocks are the length of exons, and numbers in parentheses are the length of translated regions when an exon contains a non-translated region. Note the conservation of exon arrangements of RANBP5 after D. rerio and the single exon RANBP6 in human and mouse after retroposition.
	Fig. 6. Gene expression patterns of β-karyopherins in mouse early development. The vertical axis is the log2 ratio of gene expression levels; the horizontal axis is the developmental period abbreviated as follows (days postcoitus (dpc)): T1, fertilized egg; T2, blastocysts; T3, dpc 6.5; T4, dpc 7.5; T5, dpc 8.5; T6, dpc 9.5; and T7, dpc 10.5. The gene expression of mouse β-karyopherin genes was grouped into six patterns: a, Cse1l, Ipo4, Ipo7, Ipo11, Ipo13, Ranbp5, Tnpo2, Tnpo3, Xpo1, and Xpot; b, Ranbp6 and Xpo5; c, Tnpo1 and Xpo4; d, Ipo9 and Ranbp17; e, Kpnb1 and Xpo7; and f, Ipo8.
	Fig. 7. a Transcription factor binding sites of human β-karyopherin genes predicted by the MAPPER search engine. The regulatory analyses of the 20 β-karyopherin genes are illustrated line by line. The numbers under the lines are the positions (in bp) from the start of the transcript (position +1). The TFBSs are indicated above or beneath the lines. Five mostly potential TFBSs (SP1, NRF-2, Hen-1, RREB-1, and CAAT box) are highlighted by symbols. USF, upstream stimulatory factor; PPAR, peroxisome proliferator-activated receptor; COUP-TF, chicken ovalbumin upstream promoter-transcription factor; CREB, cAMP-response element-binding protein; RXR, retinoid X receptor; VDR, vitamin D receptor; ER, estrogen receptor; NF, nuclear factor; SRY, sex-determining region Y-chromosome protein; FTF, α-1-fetoprotein transcription factor; HLF, hepatic leukemia factor; ATF, activating transcription factor; CDP, CCAAT displacement protein; NF-GMa, nuclear factor for granulocyte/macrophage colony-stimulating factor; HLTF, helicase-like transcription factor.
	Fig. 7. b Transcription factor binding sites of human β-karyopherin genes predicted by the MAPPER search engine. The regulatory analyses of the 20 β-karyopherin genes are illustrated line by line. The numbers under the lines are the positions (in bp) from the start of the transcript (position +1). The TFBSs are indicated above or beneath the lines. Five mostly potential TFBSs (SP1, NRF-2, Hen-1, RREB-1, and CAAT box) are highlighted by symbols. USF, upstream stimulatory factor; PPAR, peroxisome proliferator-activated receptor; COUP-TF, chicken ovalbumin upstream promoter-transcription factor; CREB, cAMP-response element-binding protein; RXR, retinoid X receptor; VDR, vitamin D receptor; ER, estrogen receptor; NF, nuclear factor; SRY, sex-determining region Y-chromosome protein; FTF, α-1-fetoprotein transcription factor; HLF, hepatic leukemia factor; ATF, activating transcription factor; CDP, CCAAT displacement protein; NF-GMa, nuclear factor for granulocyte/macrophage colony-stimulating factor; HLTF, helicase-like transcription factor.
	Fig. 8. Transcription factor binding sites of XPO1 orthologous genes predicted by the MAPPER search engine. The regulatory analyses of XPO1 over species are illustrated line by line: Hs, H. sapiens; Mm, M. musculus; Gg, G. gallus; Xt, X. tropicalis; Dr, D. rerio; Dm, D. melanogaster; Ce, C. elegans; and Sc, S. cerevisiae. The numbers under the lines are the positions (in bp) from the start of the transcript (position +1). The TFBSs are indicated above or beneath the lines. TF, transcription factor; PPAR, peroxisome proliferator-activated receptor; NF, nuclear factor; Bsap, B-cell-specific activator protein. NF-GMa, nuclear factor for granulocytes/macrophage colony-stimulating factor; DREF, DNA replication-related element binding factor; Su(H), suppressor of hairless protien; SU_h, suppressor of hairless protein.

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