The Ran-binding protein 2 (RanBP2) is a vertebrate mosaic protein composed of four interspersed RanGTPase binding domains (RBDs), a variable and species-specific zinc finger cluster domain, leucine-rich, cyclophilin, and cyclophilin-like (CLD) domains. Functional mapping of RanBP2 showed that the domains, zinc finger and CLD, between RBD1 and RBD2, and RBD3 and RBD4, respectively, associate specifically with the nuclear export receptor, CRM1/exportin-1, and components of the 19 S regulatory particle of the 26 S proteasome. Now, we report the mapping of a novel RanBP2 domain located between RBD2 and RBD3, which is also conserved in the partially duplicated isoform RanBP2L1. Yet, this domain leads to the neuronal association of only RanBP2 with two kinesin microtubule-based motor proteins, KIF5B and KIF5C. These kinesins associate directly in vitro and in vivo with RanBP2. Moreover, the kinesin light chain and RanGTPase are part of this RanBP2 macroassembly complex. These data provide evidence of a specific docking site in RanBP2 for KIF5B and KIF5C. A model emerges whereby RanBP2 acts as a selective signal integrator of nuclear and cytoplasmic trafficking pathways in neurons. The Ran-binding protein 2 (RanBP2) is a vertebrate mosaic protein composed of four interspersed RanGTPase binding domains (RBDs), a variable and species-specific zinc finger cluster domain, leucine-rich, cyclophilin, and cyclophilin-like (CLD) domains. Functional mapping of RanBP2 showed that the domains, zinc finger and CLD, between RBD1 and RBD2, and RBD3 and RBD4, respectively, associate specifically with the nuclear export receptor, CRM1/exportin-1, and components of the 19 S regulatory particle of the 26 S proteasome. Now, we report the mapping of a novel RanBP2 domain located between RBD2 and RBD3, which is also conserved in the partially duplicated isoform RanBP2L1. Yet, this domain leads to the neuronal association of only RanBP2 with two kinesin microtubule-based motor proteins, KIF5B and KIF5C. These kinesins associate directly in vitro and in vivo with RanBP2. Moreover, the kinesin light chain and RanGTPase are part of this RanBP2 macroassembly complex. These data provide evidence of a specific docking site in RanBP2 for KIF5B and KIF5C. A model emerges whereby RanBP2 acts as a selective signal integrator of nuclear and cytoplasmic trafficking pathways in neurons. Ran-binding protein 1 Ran-binding protein 2 RanGTPase binding domain(s) cyclophilin-like domains 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid glutathione S-transferase polyacrylamide gel electrophoresis matrix-assisted laser desorption/ionization time-of-flight mass spectrometry zinc finger cluster domain antibody monoclonal antibody guanosine 5′-3-O-(thio)triphosphate kinesin heavy chain kinesin light chain The small nuclear GTPase, Ran, is a key regulator of protein (1Moroianu J. Blobel G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4318-4322Crossref PubMed Scopus (61) Google Scholar, 2Izaurralde E. Kutay U. von Kobbe C. Mattaj I.W. Gorlich D. EMBO J. 1997; 16: 6535-6547Crossref PubMed Scopus (494) Google Scholar, 3Richards S.A. Carey K.L. Macara I.G. Science. 1997; 276: 1842-1844Crossref PubMed Scopus (40) Google Scholar) and RNA (4Kadowaki T. Goldfarb D. Spitz L. Tartakoff A. Ohno M. EMBO J. 1993; 12: 2929-2937Crossref PubMed Scopus (154) Google Scholar, 5Cheng Y. 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This mechanism presumably ensures that loading of cargo destined for nuclear import and unloading of nuclear exported substrates, and loading of cargo for nuclear export and unloading of nuclear imported cargo, respectively, are compartmentalized in the cytosol and nucleus. The Ran-binding protein 1 (RanBP1)1 (36Coutavas E. Ren M. Oppenheim D. Eustachio P.D Rush M.G. Nature. 1993; 366: 585-587Crossref PubMed Scopus (226) Google Scholar) and Ran-binding protein 2 (RanBP2) (37Ferreira P.A. Hom J. Pak W. J. Biol. Chem. 1995; 270: 23179-23188Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 38Wilken N. Senecal J.-L. Scheer U. Dabauvalle M.-C. Eur. J. Cell Biol. 1995; 68: 211-219PubMed Google Scholar, 39Wu J. Matunis M.J. Kraemer D. Blobel G. Coutavas E. J. Biol. Chem. 1995; 270: 14209-14213Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar, 40Yokoyama N. Hayashi N. Seki T. Pante N. Ohba T. Nishii K. Kuma K. Hayashida T. Miyata T. Aebi U. Fukui M. Nishimoto T. Nature. 1995; 376: 184-188Crossref PubMed Scopus (413) Google Scholar) are two cytosolic proteins with high affinity for RanGTP (34Bischoff F. Krebber H. Smirnova E. Dong W. Ponstingl H. EMBO J. 1995; 14: 705-715Crossref PubMed Scopus (331) Google Scholar, 35Braslavsky C.I., V. Novak C. Gorlich D. Wittinghofer A. Kuhlmann J. Biochemistry. 2000; 39: 11629-11639Crossref PubMed Scopus (54) Google Scholar, 36Coutavas E. Ren M. Oppenheim D. Eustachio P.D Rush M.G. Nature. 1993; 366: 585-587Crossref PubMed Scopus (226) Google Scholar, 40Yokoyama N. Hayashi N. Seki T. Pante N. Ohba T. Nishii K. Kuma K. Hayashida T. Miyata T. Aebi U. Fukui M. Nishimoto T. Nature. 1995; 376: 184-188Crossref PubMed Scopus (413) Google Scholar, 41Ferreira P.A. Nakayama T. Pak W. Travis G. Nature. 1996; 383: 637-640Crossref PubMed Scopus (189) Google Scholar). RanBP1 is well conserved from yeast to higher eukaryotes (24Gorlich D. Kutay U. Annu. Rev. Cell Dev. 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In humans, the RanBP2 gene is partially duplicated once in chromosome 2 and designated RanBP2L1 (45Nothwang H.G. Rensing C. Kubler M. Denich D. Brandl B. Stubanus M. Haaf T. Kurnit D. Hildebrandt F. Genomics. 1998; 47: 383-392Crossref PubMed Scopus (31) Google Scholar). This gene encodes the leucine-rich domain, two (RBD2 and RBD3) of the four RBDs of RanBP2, but lacks its zinc finger cluster, W1W2 tandem repeats, RBD4, cyclophilin, and the C-terminal part of CLD domains (44Fauser S. Aslanukov A. Roepman R. Ferreira P. Mamm. Genome. 2001; 12: 406-415Crossref PubMed Scopus (11) Google Scholar). RanBP2 is highly expressed in retinal neurons (37Ferreira P.A. Hom J. Pak W. J. Biol. Chem. 1995; 270: 23179-23188Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar) and is also shown to localize at cytoplasmic fibrils emanating from the nuclear pore complex of liver cells (38Wilken N. Senecal J.-L. Scheer U. Dabauvalle M.-C. Eur. J. Cell Biol. 1995; 68: 211-219PubMed Google Scholar, 39Wu J. Matunis M.J. Kraemer D. Blobel G. Coutavas E. J. Biol. Chem. 1995; 270: 14209-14213Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar, 40Yokoyama N. Hayashi N. Seki T. Pante N. Ohba T. Nishii K. Kuma K. Hayashida T. Miyata T. Aebi U. Fukui M. Nishimoto T. Nature. 1995; 376: 184-188Crossref PubMed Scopus (413) Google Scholar). Several reports seem to implicate RanBP1 and RanBP2 in terminal steps of nuclear export and possibly, initial steps of nuclear import (10Melchior F. Guan T. Yokoyama N. Nishimoto T. Gerace L. J. Cell Biol. 1995; 131: 571-581Crossref PubMed Scopus (124) Google Scholar, 24Gorlich D. Kutay U. Annu. Rev. Cell Dev. Biol. 1999; 15: 607-660Crossref PubMed Scopus (1676) Google Scholar, 35Braslavsky C.I., V. Novak C. Gorlich D. Wittinghofer A. Kuhlmann J. Biochemistry. 2000; 39: 11629-11639Crossref PubMed Scopus (54) Google Scholar). Nuclear export transporters, such as exportin-1, form stable complexes with their nuclear cargo in the presence of RanGTP (27Fornerod M. Ohno M. Yoshida M. Mattaj I.W. Cell. 1997; 90: 1051-1060Abstract Full Text Full Text PDF PubMed Scopus (1744) Google Scholar, 46Askjaer P. Jensen T.B. Nilsson J. Englmeier L. Kjems J. J. Biol. Chem. 1998; 273: 33414-33422Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 47Floer M. Blobel G. J. Biol. Chem. 1999; 274: 16279-16286Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). These competent nuclear export complexes are thought to transverse the nuclear pore complex and dock at cytoplasmic stations at the cytosolic face of the nuclear pore complex or its vicinity (24Gorlich D. Kutay U. Annu. Rev. Cell Dev. Biol. 1999; 15: 607-660Crossref PubMed Scopus (1676) Google Scholar, 25Nakielny S. Dreyfuss G. Cell. 1999; 99: 677-690Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar). In support of this model is the observation that the zinc finger-rich cluster domain of RanBP2 constitutes a specific docking site for exportin-1, and in contrast to the association of Ran-GTP with exportin-1, leptomycin-B does not affect this interaction (48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Although progress has been made in identifying the components mediating nucleocytoplasmic transport, far less is known about how the cargoes are dispatched from (and to) the nuclear transport complexes once they exit the nucleus, disassembled/assembled into such complexes, and captured by downstream effectors involved in substrate targeting to various subcellular destinations. Recent structure-function analysis of RanBP2 (41Ferreira P.A. Nakayama T. Pak W. Travis G. Nature. 1996; 383: 637-640Crossref PubMed Scopus (189) Google Scholar, 48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 49Ferreira P. Yunfei C. Schick D. Roepman R. J. Biol. Chem. 1998; 273: 24676-24682Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar) suggests that selective domains of RanBP2 independently recruit specific molecular partners and provide a dynamic platform for the delivery (and/or reception) of cargoes to (and/or from) the downstream cytosolic components yet to be identified. RanBP2 contains several RBDs interspersed along its long primary structure. The zinc finger cluster domain (ZnF) of RanBP2 is flanked by the RBD1 and RBD2, suggesting that upon nuclear exiting and docking of exportin-1-RanGTP-cargo complexes to ZnF (48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar), one or more of the neighboring RanBDs may promote the disassembly of nuclear complexes via RanGTP hydrolysis. Similarly, we previously found (49Ferreira P. Yunfei C. Schick D. Roepman R. J. Biol. Chem. 1998; 273: 24676-24682Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar) that a domain with weak homology to the C-terminal cyclophilin domain of RanBP2, cyclophilin-like domain (CLD), which is flanked by RBD3 and RBD4, associates specifically and in a tissue-restricted fashion with components of the 19 S cap of the 26 S proteasome. This suggests that the predicted unfolding/chaperone activity of the 19 S regulatory particle (51Schubert U. Anton L. Gibbs J. Norbury C. Yewdell J. Bennink J. Nature. 2000; 404: 770-774Crossref PubMed Scopus (1) Google Scholar, 52Strickland E. Hakala K. Thomas P. DeMartino G.N. J. Biol. Chem. 2000; 275: 5565-5572Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar), in concert with RanGTP-mediated hydrolysis by the flanking RBDs, may also promote the disassembly of 19 S cap-associated cargoes, 19 S cap itself, and/or target some of the cargoes/carriers for possible degradation. In addition, if the mechanisms and components mediating the release and loading of nuclear cargo at the cytosolic face or vicinity of the nuclear pore complex are tightly coupled, and possibly subjected to regeneration, then factors mediating the delivery to, and transport from, the nuclear pore may be also subjected to analogous coupling and regenerating cycles. Such factors may also interface with nuclear shuttling components. This process is hinted, for example, by data reporting the localization at the nuclear pore complex of “atypical” proteins, such as Sec13p and related Seh1p, which have been implicated in ER to Golgi trafficking (53Pryer N.K. Salama N.R. Schekman R.W. Kaiser C.A. J. Cell Biol. 1993; 120: 865-875Crossref PubMed Scopus (120) Google Scholar, 54Siniossoglou S. Wimmer C. Rieger M. Doye V. Tekotte H. Weise C. Emig S. Segref A. Hurt E.C. Cell. 1996; 84: 265-275Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar). To gain further insight into the role of RanBP2 in the integration of signaling and nucleocytoplasmic trafficking processes, we postulated whether the segment region between the RBD2 and RBD3 of RanBP2, JX2, constitutes a novel functional domain. Here, we show that this previously unrecognized domain associates specifically, directly, and in a neuronal biased fashion with two members of kinesin heavy chain in vitro and in vivo. The implications of these findings are discussed. The ∼393-base pair EcoRI/SalI fragment encoding the junction region between the RBD2 and RBD3 domains of bovine RanBP2 (equivalent to the sequence of amino acids 1971–2102 and 2134–2265 of mouse (44Fauser S. Aslanukov A. Roepman R. Ferreira P. Mamm. Genome. 2001; 12: 406-415Crossref PubMed Scopus (11) Google Scholar) (GenBankTM accession number AF279458) and human (38Wilken N. Senecal J.-L. Scheer U. Dabauvalle M.-C. Eur. J. Cell Biol. 1995; 68: 211-219PubMed Google Scholar, 39Wu J. Matunis M.J. Kraemer D. Blobel G. Coutavas E. J. Biol. Chem. 1995; 270: 14209-14213Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar), respectively) was obtained from a digest of a 1.9-kilobase pair insert of a yeast two-hybrid (HybriZAP) clone, RP18, 2Y. Cai, B. B. Singh, A. Aslanukov, H. Zhao, and P. A. Ferreira, unpublished observations. and subcloned unidirectionally into XbaI Klenow-treated and SalI sites of the expression vector, pGEX-KG. Likewise, the ∼1311-base pair DNA fragment comprising RBD2-JX2-RBD3 of bovine RanBP2 (equivalent to the sequence of amino acids 1843–2280 and 2006–2443 of mouse (44Fauser S. Aslanukov A. Roepman R. Ferreira P. Mamm. Genome. 2001; 12: 406-415Crossref PubMed Scopus (11) Google Scholar) and human (38Wilken N. Senecal J.-L. Scheer U. Dabauvalle M.-C. Eur. J. Cell Biol. 1995; 68: 211-219PubMed Google Scholar, 39Wu J. Matunis M.J. Kraemer D. Blobel G. Coutavas E. J. Biol. Chem. 1995; 270: 14209-14213Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar), respectively) was subcloned into XbaI and SacI sites of pGEX-KG. Isolation of cDNAs encoding the motor and coiled-coil/tail domains of KIF5s (see Fig. 2 in Supplemental Material) was carried out by polymerase chain reaction from normalized mouse brain (KIF5A, KIF5C) and kidney (KIF5B) cDNAs (mouse MTC panel;CLONTECH), and respective identities were confirmed by DNA sequencing. The 5′ and 3′ pairs of primers used to amplify the motor domains of KIF5B-N and KIF5C-N, respectively, were 5′-GCTCTAGACATGGCGGACCCGGCGGAG and 5′-CCCAAGCTTAGCATCAATACTTGCTAAAGTTGCAGA, and 5′-GGAATTCCGATGGCGGATCCAGCCGAATGCAGC and 5′-CCCAAGCTTTCGCTGGGTGGTTGTCAGTGT. The 5′ and 3′ pair of primers to amplify the coiled-coil/tail domains of KIF5A-C, KIF5B-C and KIF5C-C, respectively, were 5′-GAATTCCGCAGAAAGTGGCCACCATGCTG and 5′-GCGTCGACTTAGCTGGCTGCTGTCTCTTG, 5′-GCTCTAGACGCAACTTTAGCAAGTATTGATGCTGAG and 5′-GCTCTAGATTACGACTGCTTGCCTCCACCACC, and 5′-GGAATTCCGGCCCAGAAAACGACGACACTGACA and 5′-CCCAAGCTTTTATTTCTGGTAGTGAGTAGAGTTTGAAGAGCC. All KIF5s constructs were subcloned into pGEX-KG, expressed, and purified on an AKTA explorer fast protein liquid chromatography system (Amersham Pharmacia Biotech), and whenever applicable, the fused protein moiety was cleaved off from GST with thrombin as described elsewhere (48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 49Ferreira P. Yunfei C. Schick D. Roepman R. J. Biol. Chem. 1998; 273: 24676-24682Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar). Analytical binding reactions of GST-JX2 (2.2 μm) and competitor, free JX2 (11–22 μm) proteins with retinal and other CHAPS-solubilized tissue extracts (∼2–3 mg) were performed at 4 °C followed by affinity capture and washing of GST-bound complexes exactly as described previously (48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 49Ferreira P. Yunfei C. Schick D. Roepman R. J. Biol. Chem. 1998; 273: 24676-24682Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar) for other RanBP2 screening assays. CHAPS extracts were prepared in the presence of EDTA-free protease inhibitor mixture (Roche Molecular Biochemicals). GST-bound complexes were resolved on SDS-PAGE and silver-stained as described (50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar). The bovine retinal p120 protein was purified by scaling up the analytical binding reactions ∼1000-fold. GST-bound complexes were incubated twice with elution buffer (50 mm Tris·HCl, pH 7.5, 500 mm NaCl, 2 mm CaCl2, 2 mm MgCl2, 0.2% Triton X-100, 0.1% β-mercaptoethanol) at room temperature for 10 min, and eluted p120 was concentrated and the buffer exchanged with storage buffer (50 mm Tris·HCl, pH 8.0, 0.1% β-mercaptoethanol, 10% glycerol) in Centricon-100 (Millipore) at 4 °C. Eluted samples were resolved on 7.5% SDS-PAGE, stained with Coomassie Blue, and destained, and the SDS-PAGE band containing retinal p120 was isolated. Sample and neighboring mock (blank) gel pieces were placed on prewashed Eppendorf tubes (0.1% trifluoroacetic acid, 60% acetonitrile) and washed in 50% acetonitrile, 50 mm ammonium bicarbonate and then 50% acetonitrile, 10 mm ammonium bicarbonate for 30 min on a nutator. Gel slices were dried in a SpeedVac followed by in-gel trypsin digestion (0.1 μg of trypsin/∼15 mm3 of gel in 10 mm ammonium bicarbonate) of the mock and protein samples at 37 °C for 24 h. Tryptic peptide mixtures were divided into two pools. 5 (v/v) and 95% (v/v) of the sample were subjected to MALDI-MS and Q-Tof MS/MS, respectively, for peptide mass spectra analysis and determination of peptide sequences. Peptide fingerprint analysis against NCBI and EMBL nonredundant data base was performed with Profound and PeptideSearch using a mass tolerance of ±0.012% for monoisotopic and ±0.05% for observed average masses. For Q-Tof analysis, samples were cleaned with a small packed “ZipTip.” MS/MS spectra were searched using the Sequest search program. Mass spectrometry analyses of retinal p120 were carried out at the Cancer Center Mass Spectrometry Resource Laboratory of Yale University. Two rabbit antibodies were generated against the recombinant (∼100 μg) and GST-cleaved ZnF (ZnF-20909 and ZnF-20908 antibodies) and junction region between RBD2 and RBD3, JX2 (JX-40 and JX-41 antibodies), of bovine RanBP2 (Fig. 1 a) as described elsewhere (37Ferreira P.A. Hom J. Pak W. J. Biol. Chem. 1995; 270: 23179-23188Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). Four to five booster shots were administered every 4–5 weeks. All antibodies were purified against the cognate-purified antigens under non-denaturing conditions according to the manufacturer’s instructions (Stereogene, Arcadia, CA). Affinity-purified antibodies, ZnF-20909 and ZnF-20908, and JX-40 and JX-41, respectively, were used at 0.4 and 0.3 ng/ml. H1 and H2 (gift of George Bloom, University of Virginia) and L2 (Chemicon, Temecula, CA), monoclonal antibodies against purified bovine brain kinesin heavy and light chains (55Pfister K.K. Wagner M.C. Stenoien D.A. Brady S.T. Bloom G.S. J. Cell Biol. 1989; 108: 1453-1463Crossref PubMed Scopus (193) Google Scholar), respectively, were used at 400 ng/ml. Bsp-36 and Pcp-42 polyclonal antisera (gift from Ron Vale, University of California, San Francisco) raised against the recombinant neuron-specific (KIF5A) and ubiquitous (KIF5B) conventional kinesin heavy chains (56Niclas J. Navone F. Hombooher N. Vale R.D. Neuron. 1994; 12: 1059-1072Abstract Full Text PDF PubMed Scopus (134) Google Scholar), respectively, were used at 1:5,000. Anti-Ran monoclonal antibody (Transduction Laboratories, Lexington, KY) was used at 1:5,000 dilution. The secondary antibody, goat anti-rabbit IgG (Jackson ImmunoResearch Laboratories Inc., West Grove, PA), was used at 25 ng/ml, and the blots were developed with the SuperSignal chemiluminescence substrate (Pierce). CHAPS-solubilized bovine extracts of different tissues and bovine and human retinal homogenates were prepared and concentrations determined exactly as described previously (50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar, 57Roepman R. Bernoud N. Schick D. Maugeri A. Berger W. Hans-Hilger R. Cremers F. Ferreira P. Hum. Mol. Genet. 2000; 9: 2095-2105Crossref PubMed Scopus (158) Google Scholar). Western blot analysis of tissues extracts and all analytical binding reactions with various GST-fused constructs (2.2 μm) were carried out exactly as described previously (48Singh B. Patel H. Roepman R. Schick D. Ferreira P. J. Biol. Chem. 1999; 274: 37370-37378Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 49Ferreira P. Yunfei C. Schick D. Roepman R. J. Biol. Chem. 1998; 273: 24676-24682Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 50Ferreira P.A. Methods Enzymol. 2000; 316: 455-468Crossref Google Scholar) for silver-stain analysis of binding reactions. In vitro association assays between recombinant GST-fused domains of KIF5 isoforms and unfused JX2 of RanBP2 were performed under similar conditions in CHAPS incubation buffer as described. Antibodies were incubated with protein A-agarose beads in a phosphate-saline buffer, pH 7.4, for 30 min. The beads were precipitated and washed 3 times with 10 volumes of phosphate-buffered saline. Immunoprecipitation assays were carried out with retinal extracts solubilized in Nonidet P-40 homogenization buffer (1% Nonidet P-40, 150 NaCl, 50 mm Tris·HCl, pH 8.0) without β-mercaptoethanol as described previously (57Roepman R. Bernoud N. Schick D. Maugeri A. Berger W. Hans-Hilger R. Cremers F. Ferreira P. Hum. Mol. Genet. 2000; 9: 2095-2105Crossref PubMed Scopus (158) Google Scholar). 10 μg of anti-RanBP2 and 6 μg and 2 μl of kinesin monoclonal and polyclonal antibodies, respectively, were used per 8 μl of protein A-agarose beads to immunocapture cognate retinal complexes. H1-bound immunocomplexes were indire
The multi-layered cell envelope structure of Gram-negative bacteria represents significant physical and chemical barriers for short-tailed phages to inject phage DNA into the host cytoplasm. Here we show that a DNA-injection protein of bacteriophage Sf6, gp12, forms a 465-kDa, decameric assembly in vitro. The electron microscopic structure of the gp12 assembly shows a ~150-Å, mushroom-like architecture consisting of a crown domain and a tube-like domain, which embraces a 25-Å-wide channel that could precisely accommodate dsDNA. The constricted channel suggests that gp12 mediates rapid, uni-directional injection of phage DNA into host cells by providing a molecular conduit for DNA translocation. The assembly exhibits a 10-fold symmetry, which may be a common feature among DNA-injection proteins of P22-like phages and may suggest a symmetry mismatch with respect to the 6-fold symmetric phage tail. The gp12 monomer is highly flexible in solution, supporting a mechanism for translocation of the protein through the conduit of the phage tail toward the host cell envelope, where it assembles into a DNA-injection device.
Brown adipose tissue (BAT) is important in monitoring energy homeostasis and cancer cachexia. Different from white adipose tissue, BAT is characterized by the presence of a large number of mitochondria in adipocytes. Translocator protein 18 kDa (TSPO), a critical transporter, is expressed in the outer membrane of mitochondria. We speculated that [18F]DPA714, a specific TSPO tracer, may monitor BAT activity in tumor-bearing mice in vivo. We first analyzed the radioactive uptake of positron emission tomography (PET) tracers in BAT of CT26 xenograft mice with 18F-fluorodeoxyglucose ([18F]FDG) and [18F]DPA714. We also studied the BAT uptake of [18F]DPA714 in CT26, A549 and LLC tumor models. The dynamic distribution of [18F]FDG is quite variable among animals, even in mice of the same tumor model (%ID/g-mean: mean ± SDM, 8.61 ± 8.90, n = 16). Contrarily, [18F]DPA714 produced high-quality and stable BAT imaging in different tumor models and different animals of the same model. Interestingly, %ID/g-mean of [18F]DPA714 in BAT was significantly higher on day 26 than that on day 7 in CT26 xenograft model. Taken together, these results strongly indicate the potential feasibility of [18F]DPA714 PET imaging in investigating BAT and energy metabolism during tumor progression in preclinical and clinical study.
A practical and efficient parallel method has been developed for the synthesis of 1,5-benzodiazepin-2-ones with a large variety of substituents at the 3-, 4-, 5-, 7-, and 8-positions using 1,5-difluoro-2,4-dinitrobenzene as the starting material. All the reactions involved here are highly effective in giving the desired products under mild conditions.
ABSTRACT Herpes simplex virus 1 (HSV-1), the prototypic member of herpesviruses, employs a virally encoded molecular machine called terminase to package the viral double-stranded DNA (dsDNA) genome into a preformed protein shell. The terminase contains a large subunit that is thought to cleave concatemeric viral DNA during the packaging initiation and completion of each packaging cycle and supply energy to the packaging process via ATP hydrolysis. We have determined the X-ray structure of the C-terminal domain of the terminase large-subunit pUL15 (pUL15C) from HSV-1. The structure shows a fold resembling those of bacteriophage terminases, RNase H, integrases, DNA polymerases, and topoisomerases, with an active site clustered with acidic residues. Docking analysis reveals a DNA-binding surface surrounded by flexible loops, indicating considerable conformational changes upon DNA binding. In vitro assay shows that pUL15C possesses non-sequence-specific, Mg 2+ -dependent nuclease activity. These results suggest that pUL15 uses an RNase H-like, metal ion-mediated catalysis mechanism for cleavage of viral concatemeric DNA. The structure reveals extra structural elements in addition to the RNase H-like fold core and variations in local architecture of the nuclease active site, which are conserved in herpesvirus terminases and bear great similarity to the phage T4 gp17 but are distinct from podovirus and siphovirus orthologs and cellular RNase H, delineating a new evolutionary lineage among a large family of eukaryotic viruses and simple and complex prokaryotic viruses.
Many DNA viruses use powerful molecular motors to cleave concatemeric viral DNA into genome-length units and package them into preformed procapsid powered by ATP hydrolysis. Here we report the structures of the DNA-packaging motor gp2 of bacteriophage Sf6, which reveal a unique clade of RecA-like ATPase domain and an RNase H-like nuclease domain tethered by a regulatory linker domain, exhibiting a strikingly distinct domain arrangement. The gp2 structures complexed with nucleotides reveal, at the atomic detail, the catalytic center embraced by the ATPase domain and the linker domain. The gp2 nuclease activity is modulated by the ATPase domain and is stimulated by ATP. An extended DNA-binding surface is formed by the linker domain and the nuclease domain. These results suggest a unique mechanism for translation of chemical reaction into physical motion of DNA and provide insights into coordination of DNA translocation and cleavage in a viral DNA-packaging motor, which may be achieved via linker-domain–mediated interdomain communication driven by ATP hydrolysis.
Objective
To investigate the correlation between angiotensin converting enzyme 2 (ACE2) gene polymorphism and left atrial enlargement in Uygur and Han patients with essential hypertension (EH) patients and their differences.
Methods
A total of 324 hypertensive patients (102 cases of Uygur and 222 cases of Han nationality) from Uygurpopulation of Kashgar in Xinjiang Uygur autonomous region and Han population of Guangzhou in Guangdong province were included as thehypertension group, and 212 healthy subjects from the corresponding areas (96 cases of Uygur and 116 cases of Han nationality) were included as the control group. The ACE2 gene (rs879922) polymorphismwas determined by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) .
Results
There were no statistically significant differences in the distribution of the genotype (P=0.546) and allele (P=0.777) of the ACE2 gene (rs879922) polymorphism between the non-hypertensive population and hypertensive Han population of Guangzhou in Guangdong province, whereas there were statistically significant differences in the distribution of the genotype (P=0.000) and allele (P=0.000) between the non-hypertensive population and hypertensive Uygur population of Kashgar inXinjiang. GG genotype in Uygur hypertensive population was significantly higher than that in non-hypertensive population. Multivariate logistic regression analysis showed that the risk of hypertension in the population with CG genotype was higher than that in the population with CC allele (OR=10.322, 95%CI: 2.247-47.425, P=0.003) . Furthermore, in the Uygur hypertensive population, the size of left atrial diameter in Uygur hypertensive population with CG genotype (3.67±0.43) was significantly enlarged compared with that in patients with CC genotype (3.08±0.35) and GG genotype (3.15±0.40) (P=0.003) . There were no statistically significant differences in Uygur non-hypertensive population with CC, CG and GG genotypes (2.93±0.36, 2.95±0.08, 2.93±0.32) (P=0.985) .
Conclusions
The ACE2 gene (rs879922) polymorphism is correlated with hypertension in Uygur population. Its CG genotype is also associated with left atrial enlargement induced byearly target organ damage, which is a hypertension susceptible gene in Uygur.
Key words:
Gene polymorphism; Uygur nationality; Han nationality; Essential hypertension; Left atrial enlargement
The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.
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