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zy1983铜虫 (小有名气)
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[其他]【原创】Cell, Vol. 126, Iss. 5, 2006 目录与摘要
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Volume 126, Issue 5, Pages 813-1004 (8 September 2006) Leading Edge 1. In This Issue • MISCELLANEOUS Pages 813-815 Abstract 2. Developmental Biology Select • MISCELLANEOUS Pages 817-819 Abstract The Hox genes encode homeodomain transcription factors that are crucial for body patterning during development. Hox genes exist in clusters and their chromosomal order mimics their spatial and temporal order of expression during embryonic development. This issue's Developmental Biology Select examines recent studies that shed further light on the key roles of Hox genes and their relatives during development and evolution. Commentary 3. Research Collaborations: Trial, Trust, and Truth • DISCUSSION Pages 823-825 Philip C. Hanawalt Abstract Successful advances in biomedical research increasingly require multigroup collaborations and publication of results in multiauthored papers. It is essential to consider at the outset how to maximize the value of such collaborations while avoiding potential pitfalls. Previews 4. Targeting Protein Stability with a Small Molecule • SHORT SURVEY Pages 827-829 Michael A. Lampson and Tarun M. Kapoor Abstract Both genetic approaches and small-molecule inhibitors can be used to perturb protein function. Banaszynski et al. (2006) now describe a strategy to regulate the stability of a target protein, in which specificity is provided by a genetically encoded tag and temporal control is imparted by a small molecule. 5. Signaling by Transmembrane Proteins Shifts Gears • SHORT SURVEY Pages 829-831 Masayori Inouye Abstract The HAMP domain is present in a large number of transmembrane proteins in prokaryotes including histidine kinases, adenylyl cyclases, chemotaxis receptors, and phosphatases. In this issue of Cell, Hulko et al. (2006) report the NMR structure of a HAMP domain and present data suggesting that it transduces signals through a simple rotation of its four-helix parallel coiled coil. 6. Plant Pathogens Trick Guard Cells into Opening the Gates • SHORT SURVEY Pages 831-834 Paul Schulze-Lefert and Silke Robatzek Abstract The stomata of plants regulate gas exchange and water transpiration in response to changing environmental conditions. New work reveals that stomata also have an important role in host defense. In this issue of Cell, Melotto et al. (2006) show that stomata close upon detection of potential microbial pathogens to prevent the infection of the leaf interior. Moreover, pathogenic bacteria have evolved strategies to suppress the closure of stomata. 7. Mind the GAP: Wnt Steps onto the mTORC1 Train • SHORT SURVEY Pages 834-836 Andrew Y. Choo, Philippe P. Roux and John Blenis Abstract The TSC1/2 tumor-suppressor complex controls protein synthesis through the regulation of mTOR. In this issue of Cell, Inoki et al. (2006) report that the kinases GSK3 and AMPK cooperate in the activation of TSC2 to inhibit mTOR activity. Surprisingly, the phosphorylation of TSC2 by GSK3 is markedly suppressed by Wnt signaling. This suggests that components of the mTOR pathway may be therapeutic targets for diseases linked to hyperactive Wnt signaling. 8. Insulin Secretion: SIRT4 Gets in on the Act • SHORT SURVEY Pages 837-839 Carmen Argmann and Johan Auwerx Abstract Despite their initial characterization as histone deacetylases controlling transcription, sirtuins also turn out to be critical regulators of metabolism. In this issue of Cell, Haigis et al. (2006) demonstrate that the mammalian Sir2 homolog SIRT4 acts in the mitochondria of pancreatic β cells to repress the activity of glutamate dehydrogenase through ADP-ribosylation. In this way, SIRT4 downregulates insulin secretion by β cells in response to amino acids. Essay 9. Nothing in Glycobiology Makes Sense, except in the Light of Evolution • SHORT SURVEY Pages 841-845 Ajit Varki Abstract The remarkable structural diversity of glycans in nature, and their roles in cellular processes, host-pathogen interactions, biological diversity and speciation can be explained by evolutionary processes. Minireviews 10. Bacterial Glycans: Key Mediators of Diverse Host Immune Responses • SHORT SURVEY Pages 847-850 Laurie E. Comstock and Dennis L. Kasper Abstract Recent studies have shown that the synthesis of various polysaccharides by bacteria can induce immune responses that are beneficial to the bacterium, the host, or both. Here, we discuss the diverse interactions between bacterial glycans and the host immune system. 11. Chemical Technologies for Probing Glycans • SHORT SURVEY Pages 851-854 Jennifer A. Prescher and Carolyn R. Bertozzi Abstract Glycans are central to many biological processes, but efforts to define their functions at the molecular level have been frustrated by a lack of suitable technologies. Here we highlight chemical tools that are beginning to address this need. Review 12. Glycosylation in Cellular Mechanisms of Health and Disease • REVIEW ARTICLE Pages 855-867 Kazuaki Ohtsubo and Jamey D. Marth Abstract Glycosylation produces an abundant, diverse, and highly regulated repertoire of cellular glycans that are frequently attached to proteins and lipids. The past decade of research on glycan function has revealed that the enzymes responsible for glycosylation—the glycosyltransferases and glycosidases—are essential in the development and physiology of living organisms. Glycans participate in many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. This review discusses the increasingly sophisticated molecular mechanisms being discovered by which mammalian glycosylation governs physiology and contributes to disease. Articles 13. Yersinia Virulence Depends on Mimicry of Host Rho-Family Nucleotide Dissociation Inhibitors • ARTICLE Pages 869-880 Gerd Prehna, Maya I. Ivanov, James B. Bliska and C. Erec Stebbins Abstract Summary Yersinia spp. cause gastroenteritis and the plague, representing historically devastating pathogens that are currently an important biodefense and antibiotic resistance concern. A critical virulence determinant is the Yersinia protein kinase A, or YpkA, a multidomain protein that disrupts the eukaryotic actin cytoskeleton. Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases. YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption. In cell culture experiments, the kinase and the GDI domains of YpkA act synergistically to promote cytoskeletal disruption, and a Y. pseudotuberculosis mutant lacking YpkA GDI activity shows attenuated virulence in a mouse infection assay. We conclude that virulence in Yersinia depends strongly upon mimicry of host GDI proteins by YpkA. 14. Crystal Structure of the Catalytic α Subunit of E. coli Replicative DNA Polymerase III • ARTICLE Pages 881-892 Meindert H. Lamers, Roxana E. Georgescu, Sang-Gyu Lee, Mike O'Donnell and John Kuriyan Abstract Summary Bacterial replicative DNA polymerases such as Polymerase III (Pol III) share no sequence similarity with other polymerases. The crystal structure, determined at 2.3 Å resolution, of a large fragment of Pol III (residues 1–917), reveals a unique chain fold with localized similarity in the catalytic domain to DNA polymerase β and related nucleotidyltransferases. The structure of Pol III is strikingly different from those of members of the canonical DNA polymerase families, which include eukaryotic replicative polymerases, suggesting that the DNA replication machinery in bacteria arose independently. A structural element near the active site in Pol III that is not present in nucleotidyltransferases but which resembles an element at the active sites of some canonical DNA polymerases suggests that, at a more distant level, all DNA polymerases may share a common ancestor. The structure also suggests a model for interaction of Pol III with the sliding clamp and DNA. 15. The Structure of T. aquaticus DNA Polymerase III Is Distinct from Eukaryotic Replicative DNA Polymerases • ARTICLE Pages 893-904 Scott Bailey, Richard A. Wing and Thomas A. Steitz Abstract Summary The crystal structure of Thermus aquaticus DNA polymerase III α subunit reveals that the structure of the catalytic domain of the eubacterial replicative polymerase is unrelated to that of the eukaryotic replicative polymerase but rather belongs to the Polβ-like nucleotidyltransferase superfamily. A model of the polymerase complexed with both DNA and β-sliding clamp interacting with a reoriented binding domain and internal β binding site was constructed that is consistent with existing biochemical data. Within the crystal, two C-terminal domains are interacting through a surface that is larger than many dimer interfaces. Since replicative polymerases of eubacteria and eukaryotes/archaea are not homologous, the nature of the replicative polymerase in the last common ancestor is unknown. Although other possibilities have been proposed, the plausibility of a ribozyme DNA polymerase should be considered. 16. Proline Isomerization of Histone H3 Regulates Lysine Methylation and Gene Expression • ARTICLE Pages 905-916 Christopher J. Nelson, Helena Santos-Rosa and Tony Kouzarides Abstract Summary The cis-trans isomerization of proline serves as a regulatory switch in signaling pathways. We identify the proline isomerase Fpr4, a member of the FK506 binding protein family in Saccharomyces cerevisiae, as an enzyme which binds the amino-terminal tail of histones H3 and H4 and catalyses the isomerization of H3 proline P30 and P38 in vitro. We show that P38 is necessary for methylation of K36 and that isomerization by Fpr4 inhibits the ability of Set2 to methylate H3 K36 in vitro. These results suggest that the conformational state of P38, controlled by Fpr4, is important for methylation of H3K36 by Set2. Consistent with such an antagonistic role, abrogation of Fpr4 catalytic activity in vivo results in increased levels of H3K36 methylation and delayed transcriptional induction kinetics of specific genes in yeast. These results identify proline isomerization as a novel noncovalent histone modification that regulates transcription and provides evidence for crosstalk between histone lysine methylation and proline isomerization. 17. Forespore Engulfment Mediated by a Ratchet-Like Mechanism • ARTICLE Pages 917-928 Dan H. Broder and Kit Pogliano Abstract Summary A key step in bacterial endospore formation is engulfment, during which one bacterial cell engulfs another in a phagocytosis-like process that normally requires SpoIID, SpoIIM, and SpoIIP (DMP). We here describe a second mechanism involving the zipper-like interaction between the forespore protein SpoIIQ and its mother cell ligand SpoIIIAH, which are essential for engulfment when DMP activity is reduced or SpoIIB is absent. They are also required for the rapid engulfment observed during the enzymatic removal of peptidoglycan, a process that does not require DMP. These results suggest the existence of two separate engulfment machineries that compensate for one another in intact cells, thereby rendering engulfment robust. Photobleaching analysis demonstrates that SpoIIQ assembles a stationary structure, suggesting that SpoIIQ and SpoIIIAH function as a ratchet that renders forward membrane movement irreversible. We suggest that ratchet-mediated engulfment minimizes the utilization of chemical energy during this dramatic cellular reorganization, which occurs during starvation. 18. The HAMP Domain Structure Implies Helix Rotation in Transmembrane Signaling • ARTICLE Pages 929-940 Michael Hulko, Franziska Berndt, Markus Gruber, Jürgen U. Linder, Vincent Truffault, Anita Schultz, Jörg Martin, Joachim E. Schultz, Andrei N. Lupas and Murray Coles Abstract Summary HAMP domains connect extracellular sensory with intracellular signaling domains in over 7500 proteins, including histidine kinases, adenylyl cyclases, chemotaxis receptors, and phosphatases. The solution structure of an archaeal HAMP domain shows a homodimeric, four-helical, parallel coiled coil with unusual interhelical packing, related to the canonical packing by rotation of the helices. This suggests a model for the mechanism of signal transduction, in which HAMP alternates between the observed conformation and a canonical coiled coil. We explored this mechanism in vitro and in vivo using HAMP domain fusions with a mycobacterial adenylyl cyclase and an E. coli chemotaxis receptor. Structural and functional studies show that the equilibrium between the two forms is dependent on the side-chain size of residue 291, which is alanine in the wild-type protein. 19. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells • ARTICLE Pages 941-954 Marcia C. Haigis, Raul Mostoslavsky, Kevin M. Haigis, Kamau Fahie, Danos C. Christodoulou, Andrew J. Murphy, David M. Valenzuela, George D. Yancopoulos, Margaret Karow, Gil Blander et al. Abstract Summary Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1–7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic β cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in β cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR. [ Last edited by hailang_zj on 2006-11-27 at 16:57 ] |
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zy1983
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20. TSC2 Integrates Wnt and Energy Signals via a Coordinated Phosphorylation by AMPK and GSK3 to Regulate Cell Growth • ARTICLE Pages 955-968 Ken Inoki, Hongjiao Ouyang, Tianqing Zhu, Charlotta Lindvall, Yian Wang, Xiaojie Zhang, Qian Yang, Christina Bennett, Yuko Harada, Kryn Stankunas et al. Abstract Summary Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving β-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation. 21. Plant Stomata Function in Innate Immunity against Bacterial Invasion • ARTICLE Pages 969-980 Maeli Melotto, William Underwood, Jessica Koczan, Kinya Nomura and Sheng Yang He Abstract Summary Microbial entry into host tissue is a critical first step in causing infection in animals and plants. In plants, it has been assumed that microscopic surface openings, such as stomata, serve as passive ports of bacterial entry during infection. Surprisingly, we found that stomatal closure is part of a plant innate immune response to restrict bacterial invasion. Stomatal guard cells of Arabidopsis perceive bacterial surface molecules, which requires the FLS2 receptor, production of nitric oxide, and the guard-cell-specific OST1 kinase. To circumvent this innate immune response, plant pathogenic bacteria have evolved specific virulence factors to effectively cause stomatal reopening as an important pathogenesis strategy. We provide evidence that supports a model in which stomata, as part of an integral innate immune system, act as a barrier against bacterial infection. 22. Presenilins Form ER Ca2+ Leak Channels, a Function Disrupted by Familial Alzheimer's Disease-Linked Mutations • ARTICLE Pages 981-993 Huiping Tu, Omar Nelson, Arseny Bezprozvanny, Zhengnan Wang, Sheu-Fen Lee, Yi-Heng Hao, Lutgarde Serneels, Bart De Strooper, Gang Yu and Ilya Bezprozvanny Abstract Summary Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for 40% of familial AD (FAD) cases. FAD mutations and genetic deletions of presenilins have been associated with calcium (Ca2+) signaling abnormalities. We demonstrate that wild-type presenilins, but not PS1-M146V and PS2-N141I FAD mutants, can form low-conductance divalent-cation-permeable ion channels in planar lipid bilayers. In experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs), we find that presenilins account for 80% of passive Ca2+ leak from the endoplasmic reticulum. Deficient Ca2+ signaling in DKO MEFs can be rescued by expression of wild-type PS1 or PS2 but not by expression of PS1-M146V or PS2-N141I mutants. The ER Ca2+ leak function of presenilins is independent of their γ-secretase activity. Our data suggest a Ca2+ signaling function for presenilins and provide support for the “Ca2+ hypothesis of AD.” Resource 23. A Rapid, Reversible, and Tunable Method to Regulate Protein Function in Living Cells Using Synthetic Small Molecules • SHORT COMMUNICATION Pages 995-1004 Laura A. Banaszynski, Ling-chun Chen, Lystranne A. Maynard-Smith, A. G. Lisa Ooi and Thomas J. Wandless Abstract Summary Rapid and reversible methods for perturbing the function of specific proteins are desirable tools for probing complex biological systems. We have developed a general technique to regulate the stability of specific proteins in mammalian cells using cell-permeable, synthetic molecules. We engineered mutants of the human FKBP12 protein that are rapidly and constitutively degraded when expressed in mammalian cells, and this instability is conferred to other proteins fused to these destabilizing domains. Addition of a synthetic ligand that binds to the destabilizing domains shields them from degradation, allowing fused proteins to perform their cellular functions. Genetic fusion of the destabilizing domain to a gene of interest ensures specificity, and the attendant small-molecule control confers speed, reversibility, and dose-dependence to this method. This general strategy for regulating protein stability should enable conditional perturbation of specific proteins with unprecedented control in a variety of experimental settings. |
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