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Intrinsic local destabilization of the C‐terminus predisposes integrin α1 I domain to a conformational switch induced by collagen binding
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Ana Monica Nunes Jie Zhu Jacqueline Jezioro Conceição A.S.A. Minetti David P. Remeta Richard W. Farndale Samir W. Hamaia Jean Baum 《Protein science : a publication of the Protein Society》2016,25(9):1672-1681
Integrin–collagen interactions play a critical role in a myriad of cellular functions that include immune response, and cell development and differentiation, yet their mechanism of binding is poorly understood. There is increasing evidence that conformational flexibility assumes a central role in the molecular mechanisms of protein–protein interactions and here we employ NMR hydrogen–deuterium exchange (HDX) experiments to explore the impact of slower timescale dynamic events. To gain insight into the mechanisms underlying collagen‐induced conformational switches, we have undertaken a comparative study between the wild type integrin α1 I and a gain‐of‐function E317A mutant. NMR HDX results suggest a relationship between regions exhibiting a reduced local stability in the unbound I domain and those that undergo significant conformational changes upon binding. Specifically, the αC and α7 helices within the C‐terminus are at the center of such major perturbations and present reduced local stabilities in the unbound state relative to other structural elements. Complementary isothermal titration calorimetry experiments have been performed to derive complete thermodynamic binding profiles for association of the collagen‐like triple‐helical peptide with wild type α1 I and E317A mutant. The differential energetics observed for E317A are consistent with the HDX experiments and support a model in which intrinsically destabilized regions predispose conformational rearrangement in the integrin I domain. This study highlights the importance of exploring different timescales to delineate allosteric and binding events. 相似文献
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Pedro Paulo Carneiro Jacilara Concei??o Michael Macedo Viviane Magalh?es Edgar M. Carvalho Olivia Bacellar 《PloS one》2016,11(2)
Human cutaneous leishmaniasis (CL) caused by Leishmania braziliensis, presents an exaggerated Th1 response that is associated with ulcer development. Macrophages are the primary cells infected by Leishmania parasites and both reactive oxygen species (ROS) and nitric oxide (NO) are important in the control of Leishmania by these cells. The mechanism involved in the killing of L. braziliensis is not well established. In this study, we evaluate the role of ROS and NO in the control of L. braziliensis infection by monocytes from CL patients. After in vitro infection with L. braziliensis, the oxidative burst by monocytes from CL patients was higher when compared to monocytes from healthy subjects (HS). Inhibition of the ROS pathway caused a significant decrease in the oxidative burst in L. braziliensis infected monocytes from both groups. In addition, we evaluated the intracellular expression of ROS and NO in L. braziliensis-infected monocytes. Monocytes from CL patients presented high expression of ROS after infection with L. braziliensis. The expression of NO was higher in monocytes from CL patients as compared to expression in monocytes from HS. A strong positive correlation between NO production and lesion size of CL patients was observed. The inhibition of ROS production in leishmania-infected monocytes from CL patients allowed the growth of viable promastigotes in culture supernatants. Thus, we demonstrate that while production of ROS is involved in L. braziliensis killing, NO alone is not sufficient to control infection and may contribute to the tissue damage observed in human CL. 相似文献
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Fernando Almeida-Souza Flávia de Oliveira Cardoso Bruno Vinicius da Concei??o Souza Tania Zaverucha do Valle Joicy Cortez de Sá Iara dos Santos da Silva Oliveira Celeste da Silva Freitas de Souza Carla Junqueira Moragas Tellis Maria do Socorro dos Santos Chagas Maria Dutra Behrens Ana Lúcia Abreu-Silva Kátia da Silva Calabrese 《PLoS neglected tropical diseases》2016,10(8)
The absence of an effective vaccine and the debilitating chemotherapy for Leishmaniasis demonstrate the need for developing alternative treatments. Several studies conducted with Morinda citrifolia have shown various biological activities, including antileishmanial activity, however its mechanisms of action are unknown. This study aimed to analyze the in vivo activity of M. citrifolia fruit juice (Noni) against Leishmania (Leishmania) amazonensis in C57BL/6 mice. M. citrifolia fruit juice from the Brazilian Amazon has shown the same constitution of other juices produced around the world and liquid chromatography–mass spectrometry analysis identified five compounds: deacetylasperulosidic acid, asperulosidic acid, rutin, nonioside B and nonioside C. Daily intragastric treatment with Noni was carried out after 55 days of L. (L.) amazonensis infection in C57BL/6 mice. Parasitic loads, cytokine and extracellular protein matrix expressions of the lesion site were analyzed by qPCR. Histopathology of the lesion site, lymph nodes and liver were performed to evaluate the inflammatory processes. Cytokines and biochemical parameters of toxicity from sera were also evaluated. The Noni treatment at 500 mg.kg-1.day-1 for 60 days decreased the lesion size and parasitic load in the footpad infected with L. (L.) amazonensis. The site of infection also showed decreased inflammatory infiltrates and decreased cytokine expressions for IL-12, TNF-α, TGF-β and IL-10. On the other hand, Noni treatment enhanced the extracellular matrix protein expressions of collagen IV, fibronectin and laminin in the infected footpad as well collagen I and II, fibronectin and laminin in the mock-infected footpads. No toxicity was observed at the end of treatment. These data show the efficacy of Noni treatment. 相似文献
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Félix Monteiro Pereira Samuel Conceição Oliveira 《Bioprocess and biosystems engineering》2016,39(11):1717-1727
In this article, the occurrence of dead core in catalytic particles containing immobilized enzymes is analyzed for the Michaelis–Menten kinetics. An assessment of numerical methods is performed to solve the boundary value problem generated by the mathematical modeling of diffusion and reaction processes under steady state and isothermal conditions. Two classes of numerical methods were employed: shooting and collocation. The shooting method used the ode function from Scilab software. The collocation methods included: that implemented by the bvode function of Scilab, the orthogonal collocation, and the orthogonal collocation on finite elements. The methods were validated for simplified forms of the Michaelis–Menten equation (zero-order and first-order kinetics), for which analytical solutions are available. Among the methods covered in this article, the orthogonal collocation on finite elements proved to be the most robust and efficient method to solve the boundary value problem concerning Michaelis–Menten kinetics. For this enzyme kinetics, it was found that the dead core can occur when verified certain conditions of diffusion–reaction within the catalytic particle. The application of the concepts and methods presented in this study will allow for a more generalized analysis and more accurate designs of heterogeneous enzymatic reactors. 相似文献
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Martins João Paulo Rodrigues Vasconcelos Leandro Lopes de Braga Priscila da Conceição de Souza Rossini Franciele Pereira Conde Lorenzo Toscano Rodrigues Luiz Carlos de Almeida Falqueto Antelmo Ralph Gontijo Andreia Barcelos Passos Lima 《Plant Cell, Tissue and Organ Culture》2020,143(2):303-318
Plant Cell, Tissue and Organ Culture (PCTOC) - Copper (Cu) is an essential metal and both its deficiency and excess has negative effects on the growth and physiology of plants. Some plant species... 相似文献
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Rossini Franciele Pereira Martins João Paulo Rodrigues Moreira Samuel Werner Conde Lorenzo Toscano Clairvil Evens Braga Priscila da Conceição de Souza Falqueto Antelmo Ralph Gontijo Andreia Barcelos Passos Lima 《Plant Cell, Tissue and Organ Culture》2022,150(1):223-236
Plant Cell, Tissue and Organ Culture (PCTOC) - Despite having the ability to bioaccumulate trace elements such as cadmium (Cd), many species also present morphophysiological disorders that can... 相似文献