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14-3-3 proteins

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The human and bovine 14-3-3 eta protein mRNAs are highly conserved
Evolutionary conservation of the 14-3-3 protein
Expression and structural analysis of 14-3-3 proteins
Crystal structure of the zeta isoform of the 14-3-3 protein
Structure of a 14-3-3 protein and multiple signalling pathways
Chromosome assignment of human brain 14-3-3 protein eta chain
Subcellular localisation of 14-3-3 isoforms in rat brain using specific antibodies

Site of interaction of 14-3-3 protein with phosphorylated tryptophan hydroxylase
Association of a 14-3-3 protein with CMP-NeuAc:GM1 alpha 2,3-sialyltransferase
Interaction of 14-3-3 with signaling proteins is mediated by phosphoserine
Activation-modulated association of 14-3-3 proteins with Cbl
14-3-3 binding sequence in cytoplasmic domain of adhesion receptor, platelet glycoprotein Ib alpha

14-3-3 brain protein homologs in plants
The 14-3-3 proteins, BMH1 and BMH2, are essential in Saccharomyces cerevisiae
A single Arabidopsis protein has characteristics of diverse 14-3-3 homologues

Expression and structural analysis of 14-3-3 proteins.

Jones DH; Martin H; Madrazo J; Robinson KA; Nielsen P; Roseboom PH; Patel Y; Howell SA; Aitken A 


Laboratory of Protein Structure, National Institute for Medical Research, London, U.K. 


J Mol Biol 245: 375-84 (1995)

The 14-3-3 family of proteins plays a role in a wide variety of cellular functions including regulation of protein kinase C and exocytosis. Using antisera specific for the N termini of 14-3-3 isoforms described previously and an additional antiserum specific for the C terminus of epsilon isoform, protease digestion of intact 14-3-3 showed that the N-terminal half of 14-3-3 (a 16 kDa fragment) was an intact, dimeric domain of the protein. Two isoforms of 14-3-3, tau and epsilon, were expressed in E. coli and their secondary structure was shown by circular dichroism to be identical to wild-type protein, and expression of N-terminally-deleted epsilon 14-3-3 protein showed that the N-terminal 26 amino acids are important for dimerization. Intact 14-3-3 is a potent inhibitor of protein kinase C, but the N-terminal domain does not inhibit PKC activity. Site-specific mutagenesis of several regions in the tau isoform of 14-3-3, including the mutation of a putative pseudosubstrate site to a potential substrate sequence, did not alter its inhibitory activity. Intact 14-3-3 proteins are phosphorylated by protein kinase C with a low stoichiometry, but truncated isoforms are phosphorylated much more efficiently by this kinase. This may imply that the proteins may adopt a different structural conformation, possibly upon binding to the membrane, which could modulate their activity. 14-3-3 proteins are found at high concentration on synaptic plasma membranes and this binding is mediated through the N-terminal 12 kDa of 14-3-3.

Activation-modulated association of 14-3-3 proteins with Cbl in T cells

Liu YC; Elly C; Yoshida H; Bonnefoy-Berard N; Altman A


Division of Immunobiology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA


J Biol Chem 271: 14591-5 (1996)

14-3-3 proteins have recently been implicated in the regulation of intracellular signaling pathways via their interaction with several oncogene and protooncogene products. We found recently that 14-3-3 associates with several tyrosine-phosphorylated proteins and phosphatidylinositol 3-kinase (PI3-K) in T cells. We report here the identification of the 120-kDa 14-3-3tau-binding phosphoprotein present in activated T cell lysates as Cbl, a protooncogene product of unknown function which was found recently to be a major protein-tyrosine kinase (PTK) substrate, and to interact with several signaling molecules including PI3-K, in T lymphocytes. The association between 14-3-3tau and Cbl was detected both in vitro and in intact T cells and, in contrast to Raf-1, was markedly increased following T cell activation. The use of truncated 14-3-3tau fusion proteins demonstrated that the 15 C-terminal residues are required for the association between 14-3-3 and three of its target proteins, namely, Cbl, Raf-1, and PI3-K. The findings that 14-3-3tau binds both PI3-K and Cbl, together with recent reports of an association between Cbl and PI3-K, suggest that 14-3-3 dimers play a critical role in signal transduction processes by promoting and coordinating protein-protein interactions of signaling proteins.

Association of a 14-3-3 protein with CMP-NeuAc:GM1 alpha 2,3-sialyltransferase

Gao L; Gu XB; Yu DS; Yu RK; Zeng G 


Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0614, USA


Biochem Biophys Res Commun 224: 103-7 (1996)

CMP-NeuAc:GM1 alpha 2,3-sialyltransferase (ST-IV) was purified to homogeneity from rat brain. Microsequencing of the tryptic peptides derived from the purified enzyme revealed two amino acid sequences homologous to the 14-3-3 proteins. A polyclonal antibody was raised against purified ST-IV. A 33 kDa protein was co-immunoprecipitated from rat brain extracts with the anti-(ST-IV) antibody as detected by Western blot analysis. This protein was identified as a subtype of 14-3-3 family by an anti-(14-3-3) antibody. Screening of a rat brain lambda gt11 library using the anti-(ST-IV) antibody resulted in the identification of a cDNA clone coding for the subtype of 14-3-3 protein. These results indicate an association of the 14-3-3 protein with the sialyltransferase. Since the 14-3-3 protein has PKC inhibitor activities and the activity of sialyltransferases is, at least in part, regulated by PKC, the association of the 14-3-3 protein with ST-IV may indicate a role for this protein in the post-translational regulation of the sialyltransferase activity through the processes of phosphorylation and dephosphorylation.

Subcellular localisation of 14-3-3 isoforms in rat brain using specific antibodies

Martin H; Rostas J; Patel Y; Aitken A 


Laboratory of Protein Structure, National Institute for Medical Research, London, England


J Neurochem 63: 2259-65 (1994)

The 14-3-3 protein family, which is present at particularly high concentrations in mammalian brain, is known to be involved in various cellular functions, including protein kinase C regulation and exocytosis. Despite the fact that most of the 14-3-3 proteins are cytosolic, a small but significant proportion of 14-3-3 in brain is tightly and selectively associated with some membranes. Using a panel of isoform-specific antisera we find that the epsilon, eta, gamma, beta, and zeta isoforms are all present in purified synaptic membranes but absent from mitochondrial and myelin membranes. In addition, the eta, epsilon, and gamma isoforms but not the beta and zeta isoforms are associated with isolated synaptic junctions. When different populations of synaptosomes were fractionated by a nonequilibrium Percoll gradient procedure, the epsilon and gamma isoforms were present and the beta and zeta isoforms were absent from the membranes of synaptosomes sedimenting in the more dense parts of the gradient. The finding that these proteins are associated with different populations of synaptic membranes suggests that they are selectively expressed in different classes of neurones and raises the possibility that some or all of them may influence neurotransmission by regulating exocytosis and/or phosphorylation.

Evolutionary conservation of the 14-3-3 protein

Martens GJ; Piosik PA; Danen EH 


Department of Animal Physiology, University of Nijmegen, Toernooiveld, The Netherlands


Biochem Biophys Res Commun 184: 1456-9 (1992)

The novel family of 14-3-3 proteins may be involved in the regulation of neuronal activity. During our search for proteins coordinately expressed with the prohormone proopiomelanocortin in the melanotrope cells of the Xenopus intermediate pituitary gland, we cloned and sequenced a pituitary cDNA encoding a Xenopus 14-3-3 protein. Alignment of the Xenopus protein with known mammalian, Drosophila and plant 14-3-3 polypeptide and with a mammalian protein kinase C inhibitor protein revealed that the neuron-specific 14-3-3-related proteins are highly conserved (60-88%) throughout eukaryotic evolution.

The human and bovine 14-3-3 eta protein mRNAs are highly conserved in both their translated and untranslated regions

Swanson KD; Dhar MS; Joshi JG 


Department of Biochemistry, University of Tennessee, Knoxville 37996


Biochim Biophys Acta 1216: 145-8 (1993)

14-3-3 proteins form a highly conserved protein family whose members have been shown to activate tyrosine and tryptophan hydroxylases, inhibit protein kinase C and possess phospholipase A2 activity in vitro. We have isolated and analyzed a 14-3-3 protein cDNA clone (H14-3-3) from a human fetal brain cDNA library and found it to possess a high level of sequence identity with the bovine 14-3-3 eta protein cDNA in both the translated and untranslated regions, suggesting the presence of cis-regulatory elements in the untranslated regions of these mRNAs. The proteins encoded by these two cDNAs ar

e 98.4% identical. Two different sized RNA species, approx. 1.9 and 3.5 kb in size that are expressed in a variety of tissues hybridize with this cDNA. However, only the 1.9 kb RNA is detected in the fetal brain. Northern blot analysis of poly(A)+ RNA isolated from eight different human tissues shows that 14-3-3 protein mRNAs are expressed in many tissues in the body. In agreement with previous reports, the highest abundance of RNA hybridizing with this cDNA is seen in the brain.

Structure of a 14-3-3 protein and implications for coordination of multiple signalling pathways

Xiao B; Smerdon SJ; Jones DH; Dodson GG; Soneji Y; Aitken A; Gamblin SJ 


Division of Protein Structure, National Institute for Medical Research, Mill Hill, London, UK


Nature 376: 188-91 (1995)

A broad range of organisms and tissues contain 14-3-3 proteins, which have been associated with many diverse functions including critical roles in signal transduction pathways, exocytosis and cell cycle regulation. We report here the crystal structure of the human T-cell 14-3-3 isoform (tau) dimer at 2.6 A resolution. Each monomer (Mr 28K) is composed of an unusual arrangement of nine antiparallel alpha-helices organized as two structural domains. The dimer creates a large, negatively charged channel approximately 35 A broad, 35 A wide and 20 A deep. Overall, invariant residues line the interior of this channel whereas the more variable residues are distributed on the outer surface. At the base of this channel is a 16-residue segment of 14-3-3 which has been implicated in the binding of 14-3-3 to protein kinase C.

A fusicoccin binding protein belongs to the family of 14-3-3 brain protein homologs.

Korthout HA; de Boer AH
Department of Plant Physiology and Biochemistry, Vrije Universiteit, Amsterdam, The Netherlands
Plant Cell 6: 1681-92 (1994)



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