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Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
In addition to interaction with kinases, FAK may transduce signals through integrin-dependent interaction with adapter proteins such as Grb2 (localized to FAK residue Y925), SOS, and p130Cas (Cas) (150–152). Adapter proteins, which are small proteins composed almost exclusively of SH2 and SH3 domains (66) and which have no intrinsic kinase activity, may link FAK to the Ras pathway. SOS is a guanine nucleotide exchange factor (GNEF) that functions by converting inactive Ras-GDP to active Ras-GTP (153). Cas (Crk-associated tyrosine kinase substrate) is found in FACs and is likely phosphorylated by FAK and Src. Cas may serve as a docking protein that recruits additional signaling molecules, including Crk, to focal adhesions following integrin activation. Crk, which contains both SH2 and SH3 domains and may bind to C3G, a putative GNEF for Ras (152,154), has also been shown to associate with tyrosine-phosphorylated paxillin through its SH2 domain (155).
The Duffy Antigen Receptor for Chemokines
Published in Richard Horuk, Chemoattractant Ligands and Their Receptors, 2020
Richard Horuk, Stephen C. Peiper
The receptor could act as a docking protein to concentrate ligands at the cell surface for presentation to specific receptors on the appropriate immune cells. This hypothesis is supported by the autoradiographical demonstration by Rot25 that radiolabeled IL-8, injected into rats, binds to proteoglycans of post-capillary venules. In addition, a similar role has recently been described for MIP-1β,32 a member of the chemokine family that does not bind to the erythrocyte chemokine receptor. However, the possibility that chemokines bound to DARC could be presented to and activate leukocytes in the manner described above is unlikely given two recent observations. First, the ability of IL-8 to induce a Ca2+ flux in neutrophils is decreased in the presence of erythrocytes, suggesting that the erythrocyte-bound IL-8 cannot bind to or activate the neutrophil IL-8 receptor.3 Second, neutrophils in whole blood (Duffy positive and Duffy negative) were stimulated with increasing concentrations of IL-8 and the upregulation of CD11b was measured (K. Neote, personal communication). The EC50 in the presence of Duffy negative erythrocytes was 549 ±120 pM, in contrast to 119 + 23 pM for Duffy positive erythrocytes, indicating that erythrocyte-bound IL-8 was unavailable to the neutrophils.
The rab Gene Family
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Armand Tavitian, Ahmed Zahraoui
There is strong genetic evidence that SEC4 and YPT1: two small GTP-binding proteins highly related to mammalian rab proteins, are required for intracellular transport in S. cerevisiae. Thermosensitive mutations of the SEC4 gene impair the fusion of post-Golgi vesicles with the PM, suggesting that its product is required for the targeting and/or the fusion of vesicles with PM. In agreement with this, the SEC4p (p for protein) is found associated with the cytoplasmic face of vesicles in transit to the cell surface and the inner face of the PM.46 Further genetic studies have identified at least 10 genes to be essential for post-Golgi secretory events. One of these, SEC 15 localized on secretory vesicles, may be a SEC4 target. This suggests that SEC4 controls the formation of a complex between a docking protein, SEC15, and a PM target.47
Docking protein-1 promotes inflammatory macrophage signaling in gastric cancer
Published in OncoImmunology, 2019
Tong Li, Beifang Li, Asgharpour Sara, Christine Ay, Wing Yan Leung, Yanquan Zhang, Yujuan Dong, Qiaoyi Liang, Xiang Zhang, Philip Weidner, Tobias Gutting, Hans-Michael Behrens, Christoph Röcken, Joseph JY Sung, Matthias P. Ebert, Jun Yu, Elke Burgermeister
Proteins with docking, adapter or scaffold properties modify the responsiveness of gastrointestinal cancer cells to chemo- or targeted therapy in vitro7 and in vivo.8 Docking protein-1 (DOK1) belongs to a family of adapter proteins with seven members, where DOK1/2/3 form cooperative heterodimers mainly in hematopoietic cells, whereas DOK4-7 are predominant in non-hematopoietic cells like brain and muscle.9 We10 and others described DOK1 as an interaction partner and co-chaperone of transcription factors, prominent in surveillance of cell fate decisions and immunity, including nuclear factor-kappa B (NFκB)11 and peroxisome proliferator-activated receptor gamma (PPARγ).12 DOK1 also binds to the intracellular domains of immune (e.g., toll-like receptors on macrophages) or signaling receptors and alters their activities, such as oncogenic RAS signaling.9 The DOK1 gene is located on human chromosome 2p13.1 and frequently subjected to (epi)genetic alterations and silencing in human cancers.13DOK1/2/3 triple knock-out mice suffer from histiocytic sarcomas caused by aberrant proliferation of cells from the myeloid lineage, emphasizing the important role of DOK genes in innate immune cells including macrophages.14
Computational investigation of mechanistic insights of Aβ42 interactions against extracellular domain of nAChRα7 in Alzheimer’s disease
Published in International Journal of Neuroscience, 2019
Mubashir Hassan, Saba Shahzadi, Hussain Raza, Muhammad Athar Abbasi, Hany Alashwal, Nazar Zaki, Ahmed A. Moustafa, Sung-Yum Seo
MD simulation results showed the stability of protein structures by generating RMSD, RMSF, Gyration and SASA graphs. The comparative analyses of MD simulation results justified that ClusPro docking complex showed good stable results compared to HADDOCK and FireDock results in simulation time period. Moreover, RMSF results of all three docking protein structures dynamically fluctuated from residues N to C terminals (2 to 215 AA). Three fluctuation peaks higher than 0.8 nm appeared in the graph. Residues around 110 and 210 positions showed higher fluctuations in loop regions. The comparative results justify that HADDOCK loop regions showed higher fluctuations compared to ClusPro and FireDock. Furthermore, gyration and SASA results also show the significance of protein stability in binding interaction. Our MD analyses showed that conformational positions in both ClusPro and FireDock docking servers were remained stable compared to HADDOCK results. Our computational analysis showed the binding pattern of aggregated Aβ42 against nAChRα7 and their involvement in AD. Moreover, nAChRα7 could be used as novel target to design novel pharmaceutical agents against AD.
Structure-based identification of potential novel inhibitors targeting FAM3B (PANDER) causing type 2 diabetes mellitus through virtual screening
Published in Journal of Receptors and Signal Transduction, 2019
Goverdhan Lanka, Revanth Bathula, Mahendar Dasari, Sravanthi Nakkala, Manan Bhargavi, Gururaj Somadi, Sarita Rajender Potlapally
Virtual screening is a computer-based technique to analyze docking in structure-based drug design to predict binding affinity and interactions between protein–ligand complexes [43]. A library of chemical structures of compounds of asinex-elite database with a set of 10,000 small molecules was initially subjected to ligprep, which results in 14,849 minimized ligands as input database for virtual screening at the active site of target protein FAM3B for docking. The ligands of the library get prefiltered in screening through Qikprop and Lipinski rule of five (RO5). Prior to molecular docking protein has to be minimized with protein preparation wizard in Schrodinger suite using an OPLS_2005 force field. The whole protein structure gets minimized until it reaches a stable RMSD score of 0.30 Å and the total potential energy of initial model reduced from 2.51 kcal/mol to −7.03 kcal/mol. The prepared FAM3B protein and ligands of the asinex-elite library are used for docking with a 3d grid which was built using glide module by Schrodinger suite. A 3d grid was constructed as shown in Figure 12 using active site residues of FAM3B which are recovered from its homologous template 2YOQ by manual correlation analysis of sequences of query and template. Virtual screening of biological target FAM3B with input library of asinex-elite series of compounds was docked in various filtering methods of screening HTVS (High Throughput Virtual Screening), SP (Standard Precession), and XP (Extra precession) by glide virtual screening workflow in Schrodinger suite [44]. The 14849 molecules resulting from ligprep were subjected to HTVS mode of docking which screens the molecules at a fast rate. Thereafter the docked 1325 (10%) prefiltered molecules were then docked under the SP pattern of screening. The XP protocol screen the 132 (10%) top-ranked molecules obtained from SP. The final 132 ligands from SP were subjected to docking under XP. The final output from XP results in 14 (10%) molecules based on their docking scores and glide energies. Glide XP and XP descriptor information provide the visualization of the resulting final hits based on number of hydrogen bonding interactions, distances, and RMSD as tabulated in Table 4. The 3d binding orientations of lead structures from D1-D6 are visualized in discovery studio3.5 and 2d interaction diagrams are saved from Schrodinger suite shown in Figure 13. The final lead compounds were further prioritized using ADME, binding free energies and percent human oral absorption [45,46]. The superimposition of best-docked lead molecules D4, D5 and D6 into FAM3B binding pocket showing the binding selectivity towards Glu41, Glu119, Arg145, Glu146, Ile148 and Glu164 active residues (Figure 14).