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11.
Auguin D Barthe P Augé-Sénégas MT Stern MH Noguchi M Roumestand C 《Journal of biomolecular NMR》2004,28(2):137-155
The programmed cell death occurs as part of normal mammalian development. The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 3'-OH kinase (PI3K)/Protein Kinase B (PKB, also named Akt) cascade. Several targets of the PI3K/PKB signaling pathway have been identified that may underlie the ability of this regulatory cascade to promote cell survival. PKB possesses a N-terminal Pleckstrin Homology (PH) domain that binds specifically and with high affinity to PtIns(3,4,5)P(3) and PtIns(3,4)P(2), the PI3K second messengers. PKB is then recruited to the plasma membrane by virtue of its interaction with 3'-OH phosphatidylinositides and activated. Recent evidence indicates that PKB is active in various types of human cancer; constitutive PKB signaling activation is believed to promote proliferation and increased cell survival, thereby contributing to cancer progression. Thus, it has been shown that induction of PKB activity is augmented by the TCL1/MTCP1 oncoproteins through a physical association requiring the PKB PH domain. Here we present the three-dimensional solution structure of the PH domain of the human protein PKB (isoform beta). PKBbeta-PH is an electrostatically polarized molecule that adopts the same fold and topology as other PH-domains, consisting of a beta-sandwich of seven strands capped on one top by an alpha-helix. The opposite face presents three variable loops that appear poorly defined in the NMR structure. Measurements of (15)N spin relaxation times and heteronuclear (15)N[(1)H]NOEs showed that this poor definition is due to intrinsic flexibility, involving complex motions on different time scales. Chemical shift mapping studies correctly defined the binding site of Ins(1,3,4,5)P(4) (the head group of PtIns(3,4,5)P(3)), as was previously proposed from a crystallographic study. More interestingly, these studies allowed us to define a putative alternative low-affinity binding site for Ins(1,4,5)P(3). The binding of this sugar to PKBbeta-PH might also involve non-specific association that could explain the stabilization of the protein in solution in the presence of Ins(1,4,5)P(3). 相似文献
12.
Baymann F Lebrun E Brugna M Schoepp-Cothenet B Giudici-Orticoni MT Nitschke W 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2003,358(1429):267-274
Genome analyses and the resolution of three-dimensional structures have provided evidence in recent years for hitherto unexpected family relationships between redox proteins of very diverse enzymes involved in bioenergetic electron transport. Many of these enzymes appear in fact to be constructed from only a limited set of building blocks. Phylogenetic analysis of selected units from this "redox enzyme construction kit" indicates an origin for several prominent bioenergetic enzymes that is very early, lying before the divergence of Bacteria and Archaea. Possible scenarios for the early evolution of selected complexes are proposed based on the obtained tree topologies. 相似文献
13.
Abergel C Nitschke W Malarte G Bruschi M Claverie JM Giudici-Orticoni MT 《Structure (London, England : 1993)》2003,11(5):547-555
The study of electron transfer between the copper protein rusticyanin (RCy) and the c(4)-cytochrome CYC(41) of the acidophilic bacterium Acidithiobacillus ferrooxidans has evidenced a remarkable decrease of RCy's redox potential upon complex formation. The structure of the CYC(41) obtained at 2.2 A resolution highlighted a specific glutamate residue (E121) involved in zinc binding as potentially playing a central role in this effect, required for the electron transfer to occur. EPR and stopped-flow experiments confirmed the strong inhibitory effect of divalent cations on CYC(41):RCy complex formation. A docking analysis of the CYC(41) and RCy structure allows us to propose a detailed model for the complex-induced tuning of electron transfer in agreement with our experimental data, which could be representative of other copper proteins involved in electron transfer. 相似文献
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15.
QUASIMODO1 encodes a putative membrane-bound glycosyltransferase required for normal pectin synthesis and cell adhesion in Arabidopsis
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Bouton S Leboeuf E Mouille G Leydecker MT Talbotec J Granier F Lahaye M Höfte H Truong HN 《The Plant cell》2002,14(10):2577-2590
Pectins are a highly complex family of cell wall polysaccharides. As a result of a lack of specific mutants, it has been difficult to study the biosynthesis of pectins and their role in vivo. We have isolated two allelic mutants, named quasimodo1 (qua1-1 and qua1-2), that are dwarfed and show reduced cell adhesion. Mutant cell walls showed a 25% reduction in galacturonic acid levels compared with the wild type, indicating reduced pectin content, whereas neutral sugars remained unchanged. Immersion immunofluorescence with the JIM5 and JIM7 monoclonal antibodies that recognize homogalacturonan epitopes revealed less labeling of mutant roots compared with the wild type. Both mutants carry a T-DNA insertion in a gene (QUA1) that encodes a putative membrane-bound glycosyltransferase of family 8. We present evidence for the possible involvement of a glycosyltransferase of this family in the synthesis of pectic polysaccharides, suggesting that other members of this large multigene family in Arabidopsis also may be important for pectin biosynthesis. The mutant phenotype is consistent with a central role for pectins in cell adhesion. 相似文献
16.
17.
Masson P Schopfer LM Bartels CF Froment MT Ribes F Nachon F Lockridge O 《Biochimica et biophysica acta》2002,1594(2):313-324
Substrate inhibition is considered a defining property of acetylcholinesterase (AChE), whereas substrate activation is characteristic of butyrylcholinesterase (BuChE). To understand the mechanism of substrate inhibition, the pH dependence of acetylthiocholine hydrolysis by AChE was studied between pH 5 and 8. Wild-type human AChE and its mutants Y337G and Y337W, as well as wild-type Bungarus fasciatus AChE and its mutants Y333G, Y333A and Y333W were studied. The pH profile results were unexpected. Instead of substrate inhibition, wild-type AChE and all mutants showed substrate activation at low pH. At high pH, there was substrate inhibition for wild-type AChE and for the mutant with tryptophan in the pi-cation subsite, but substrate activation for mutants containing small residues, glycine or alanine. This is particularly apparent in the B. fasciatus AChE. Thus a single amino acid substitution in the pi-cation site, from the aromatic tyrosine of B. fasciatus AChE to the alanine of BuChE, caused AChE to behave like BuChE. Excess substrate binds to the peripheral anionic site (PAS) of AChE. The finding that AChE is activated by excess substrate supports the idea that binding of a second substrate molecule to the PAS induces a conformational change that reorganizes the active site. 相似文献
18.
19.
Induction of cytolytic T lymphocytes by immunization of mice with an adenovirus containing a mouse homolog of the human MAGE-A genes 总被引:3,自引:0,他引:3
Van Pel A De Plaen E Duffour MT Warnier G Uyttenhove C Perricaudet M Boon T 《Cancer immunology, immunotherapy : CII》2001,49(11):593-602
The genes of the MAGE-A family code for antigens that are strictly tumor-specific and are shared by many human tumors. Melanoma patients have been
immunized against these antigens and some tumor regressions have been observed. However, no unequivocal evidence of cytolytic
T cell responses has been obtained by analyzing the blood lymphocytes of these patients. Hence it was considered worthwhile
to examine in mouse systems whether or not immunization against antigens derived from the mouse Mage homologs can produce
cytolytic T cell responses. We have identified an antigenic peptide encoded by mouse gene Mage-a2, and here we show that immunization of DBA/2 mice with a recombinant adenovirus containing either just the sequence encoding
this peptide or a large part of the Mage-a2 coding sequence produces strong cytolytic T cell responses. The Mage-a2 system should prove useful for the comparison of
vaccination modalities that could be applied to human patients in therapeutic vaccination trials with MAGE antigens.
Received: 1 June 2000 / Accepted: 17 August 2000 相似文献
20.
Bruno Chauffert Marie-Thérèse Dimanche-Boitrel Carmen Garrido Mikael Ivarsson Monique Martin François Martin Eric Solary 《Cytotechnology》1998,27(1-3):225-235
Kinetic resistance plays a major role in the failure of chemotherapy towards many solid tumors. Kinetic resistance to cytotoxic
drugs can be reproduced in vitro by growing the cells as multicellular spheroids (Multicellular Resistance) or as hyperconfluent
cultures (Confluence-Dependent Resistance). Recent findings on the cell cycle regulation have permitted a better understanding
why cancer cells which arrest in long quiescent phases are poorly sensitive to cell-cycle specific anticancer drugs. Two cyclin-dependent
kinase inhibitors (CDKI) seem particularly involved in the cell cycle arrest at the G1 to S transition checkpoint: the p53-dependent
p21cip1 protein which is activated by DNA damage and the p27kip1 which is a mediator of the contact inhibition signal. Cell quiescence could alter drug-induced apoptosis which is partly
dependent on an active progression in the cell cycle and which is facilitated by overexpression of oncogenes such as c-Myc
or cyclins. Investigations are yet necessary to determine the influence of the cell cycle on the balance between antagonizing
(bcl-2, bcl-XL...) or stimulating (Bax, Bcl-XS, Fas...) factors in chemotherapy-induced apoptosis. Quiescent cells could also be protected from toxic agents by an enhanced
expression of stress proteins, such as HSP27 which is induced by confluence. New strategies are required to circumvent kinetic
resistance of solid tumors: adequate choice of anticancer agents whose activity is not altered by quiescence (radiation, cisplatin),
recruitment from G1 to S/G2 phases by cell pretreatment with alkylating drugs or attenuation of CDKI activity by specific
inhibitors.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献