PubMed · 5657279
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J J Blais, P H Geil. 1968. Fibrillar polypeptide aggregates.. https://doi.org/10.1016/s0022-5320(68)90023-3
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Transforming growth factor (TGF)-beta1, a pleiotropic cytokine involved in regulating growth and differentiation, can exert both pro-apoptotic and anti-apoptotic effects depending on the cell type or circumstances. We observed that TGF-beta1 blocked apoptosis resulting from serum withdrawal in A549 human lung carcinoma cells. This was associated with suppression of JNK activation that occurs concomitant with the onset of apoptosis in the absence of TGF-beta1, suggesting that JNK plays an active role in the death process and that TGF-beta1 exerts its protective influence by altering JNK activity. Overexpression of a dominant negative mutant form of SEK1, an upstream activator of JNK, likewise suppressed JNK activation and inhibited apoptosis. Investigation of early events following TGF-beta1 treatment revealed an early induction and phosphorylation of c-Jun that was absent in cells subjected to serum withdrawal alone. That TGF-beta1-induced expression of c-Jun is important for survival was supported by the finding that overexpression of non-phosphosphorylatable dominant negative mutant c-Jun, c-Jun(S73A), attenuated the protective influence of TGF-beta1. Our findings suggest that JNK activation is a late but essential event in serum deprivation-induced apoptosis in A549 cells. TGF-beta1 prevents apoptosis, in part, through the early induction and phosphorylation of c-Jun, which in turn results in attenuated JNK activation.
Simulated ir absorption and vibrational CD (VCD) spectra of four alanine-based octapeptides, each having its main chain constrained to a different secondary structure conformation, were analyzed and compared with experimental results for several different peptides. The octapeptide simulations were based on transfer of property tensors from a series of ab initio calculations for a short L-alanine based segment containing 3 peptide bonds with relative straight phi, psi angles fixed to those appropriate for alpha-helix, 3(10)-helix, ProII-like helix, and beta-sheet-like strand. The tripeptide force field (FF) and atomic polar tensors were obtained with density functional theory techniques at the BPW91/6-31G** level and the atomic axial tensor at the mixed BPW91/6-31G**/HF/6-31G level. Allowing for frequency correction due to the FF limitations, the octapeptide results obtained are qualitatively consistent with experimental observations for ir and VCD spectra of polypeptides and oligopeptides in established conformations. In all cases, the correct VCD sign patterns for the amide I and II bands were predicted, but the intensities did have some variation from the experimental patterns. Predicted VCD changes upon deuteration of either the peptide or side-chains as well as for (13)C isotopic labeling of the amide C=O at specific sites in the peptide chain were computed for analysis of experimental observations. A combination of theoretical modeling with experimental data for labeled compounds leads both to enhanced resolution of component transitions and added conformational applicability of the VCD spectra.
TNK-tissue plasminogen activator (TNK-t-PA), a bioengineered variant of tissue-type plasminogen activator (t-PA), has a longer half-life than t-PA because the glycosylation site at amino acid 117 (N117Q, abbreviated N) has been shifted to amino acid 103 (T103N, abbreviated T) and is resistant to inactivation by plasminogen activator inhibitor 1 because of a tetra-alanine substitution in the protease domain (K296A/H297A/R298A/R299A, abbreviated K). TNK-t-PA is more fibrin-specific than t-PA for reasons that are poorly understood. Previously, we demonstrated that the fibrin specificity of t-PA is compromised because t-PA binds to (DD)E, the major degradation product of cross-linked fibrin, with an affinity similar to that for fibrin. To investigate the enhanced fibrin specificity of TNK-t-PA, we compared the kinetics of plasminogen activation for t-PA, TNK-, T-, K-, TK-, and NK-t-PA in the presence of fibrin, (DD)E or fibrinogen. Although the activators have similar catalytic efficiencies in the presence of fibrin, the catalytic efficiency of TNK-t-PA is 15-fold lower than that for t-PA in the presence of (DD)E or fibrinogen. The T and K mutations combine to produce this reduction via distinct mechanisms because T-containing variants have a higher K(M), whereas K-containing variants have a lower k(cat) than t-PA. These results are supported by data indicating that T-containing variants bind (DD)E and fibrinogen with lower affinities than t-PA, whereas the K and N mutations have no effect on binding. Reduced efficiency of plasminogen activation in the presence of (DD)E and fibrinogen but equivalent efficiency in the presence of fibrin explain why TNK-t-PA is more fibrin-specific than t-PA.