scholarly journals A Complex Interplay of Anionic Phospholipid Binding Regulates 3’-Phosphoinositide-Dependent-Kinase-1 Homodimer Activation

2019 ◽  
Author(s):  
Gloria de las Heras-Martínez ◽  
Véronique Calleja ◽  
Remy Bailly ◽  
Jean Dessolin ◽  
Banafshé Larijani ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Pi3k Pathway ◽  
Ph Domain ◽  
Anionic Phospholipid ◽  
Direct Role ◽  
Time Resolved ◽  
Anionic Phospholipids ◽  
Spatio Temporal ◽  
Time Resolved Imaging ◽  
Phosphoinositide Dependent Kinase

Abstract3’-Phosphoinositide-dependent-Kinase-1 is a master regulator whereby its PI3-kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for PtdIns(3,4,5)P3 and other anionic phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete.Using advanced quantitative-time-resolved imaging, FCS and molecular modelling, we show an interplay of antagonistic binding effects of PtdIns(3,4,5)P3 and other anionic phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal and conformational dynamics of PDK1 and the activation of its downstream substrates.We establish an anionic-phospholipid-dependent model for PDK1 regulation, depicting the conformational dynamics of multiple homodimer states. The dysregulation of the PI3K pathway perturbs equilibrium between the PDK1 homodimer conformations. Our findings indicate that the alteration of specific basic residues of PDK1-PH domain leads to its constitutive activation, a potential significance in different types of carcinomas.

scholarly journals A Complex Interplay of Anionic Phospholipid Binding Regulates 3′-Phosphoinositide-Dependent-Kinase-1 Homodimer Activation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gloria de las Heras-Martínez ◽  
Véronique Calleja ◽  
Remy Bailly ◽  
Jean Dessolin ◽  
Banafshé Larijani ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Pi3k Pathway ◽  
Correlation Spectroscopy ◽  
Fluorescence Lifetime Imaging ◽  
Anionic Phospholipid ◽  
Direct Role ◽  
Time Resolved ◽  
Anionic Phospholipids ◽  
Spatio Temporal ◽  
Phosphoinositide Dependent Kinase

Abstract 3′-Phosphoinositide-dependent-Kinase-1 (PDK1) is a master regulator whereby its PI3-kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for PtdIns(3,4,5)P3 and other anionic phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete. Using advanced quantitative-time-resolved imaging (Fluorescence Lifetime Imaging and Fluorescence Correlation Spectroscopy) and molecular modelling, we show an interplay of antagonistic binding effects of PtdIns(3,4,5)P3 and other anionic phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal and conformational dynamics of PDK1 and the activation of its downstream substrates. We have established a new anionic-phospholipid-dependent model for PDK1 regulation, depicting the conformational dynamics of multiple homodimer states. We show that the dysregulation of the PI3K pathway perturbs equilibrium between the PDK1 homodimer conformations. Our findings provide a role for the PtdSer binding site and its previously unrewarding role in PDK1 downregulation, suggesting a possible therapeutic strategy where the constitutively active dimer conformer of PDK1 may be rendered inactive by small molecules that drive it to its PtdSer-bound conformer.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

scholarly journals Size-Tunable Paclitaxel Nanoparticles Stabilized by Anionic Phospholipids for Transdermal Delivery Applications

2020 ◽  
Vol 15 (3) ◽  
pp. 1934578X1990068
Author(s):  
Noriyuki Uchida ◽  
Masayoshi Yanagi ◽  
Hiroki Hamada
Keyword(s):  
Stratum Corneum ◽  
Transdermal Delivery ◽  
Skin Tissue ◽  
Composite Nanoparticles ◽  
Rat Skin ◽  
Cooling Process ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Subsequent Heating

Composite nanoparticles composed of an anionic phospholipid of 1,2-dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG) and paclitaxel (PTX) were successfully prepared by mixing them in water followed by a subsequent heating/cooling process. The size of DPPG-PTX nanoparticle could be easily tuned by ultrasonic fragmentation. Upon addition of small-sized fluorescently labeled paclitaxel (FLPTX) nanoparticles with DPPG (DPPG-FLPTX) to rat skin tissue, part of the FLPTX molecules permeated to the stratum corneum.

scholarly journals Giant enhancement of THz-frequency optical nonlinearity by phonon polariton in ionic crystals

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yao Lu ◽  
Qi Zhang ◽  
Qiang Wu ◽  
Zhigang Chen ◽  
Xueming Liu ◽  
...  
Keyword(s):  
Near Infrared ◽  
Optical Nonlinearity ◽  
Ionic Crystals ◽  
Nonlinear Optical Susceptibility ◽  
Time Resolved ◽  
Light Coupling ◽  
Tremendous Progress ◽  
Fundamental Research ◽  
Ionic Contribution ◽  
Time Resolved Imaging

AbstractThe field of nonlinear optics has grown substantially in past decades, leading to tremendous progress in fundamental research and revolutionized applications. Traditionally, the optical nonlinearity for a light wave at frequencies beyond near-infrared is observed with very high peak intensity, as in most materials only the electronic nonlinearity dominates while ionic contribution is negligible. However, it was shown that the ionic contribution to nonlinearity can be much larger than the electronic one in microwave experiments. In the terahertz (THz) regime, phonon polariton may assist to substantially trigger the ionic nonlinearity of the crystals, so as to enhance even more the nonlinear optical susceptibility. Here, we experimentally demonstrate a giant second-order optical nonlinearity at THz frequency, orders of magnitude higher than that in the visible and microwave regimes. Different from previous work, the phonon-light coupling is achieved under a phase-matching setting, and the dynamic process of nonlinear THz generation is directly observed in a thin-film waveguide using a time-resolved imaging technique. Furthermore, a nonlinear modification to the Huang equations is proposed to explain the observed nonlinearity enhancement. This work brings about an effective approach to achieve high nonlinearity in ionic crystals, promising for applications in THz nonlinear technologies.

scholarly journals A data reduction and compression description for high throughput time-resolved electron microscopy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Abhik Datta ◽  
Kian Fong Ng ◽  
Deepan Balakrishnan ◽  
Melissa Ding ◽  
See Wee Chee ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Temporal Resolution ◽  
Data Reduction ◽  
Accurate Estimation ◽  
Data Streaming ◽  
Compression Scheme ◽  
Raw Data ◽  
Time Resolved ◽  
Detection And Counting ◽  
Spatio Temporal

AbstractFast, direct electron detectors have significantly improved the spatio-temporal resolution of electron microscopy movies. Preserving both spatial and temporal resolution in extended observations, however, requires storing prohibitively large amounts of data. Here, we describe an efficient and flexible data reduction and compression scheme (ReCoDe) that retains both spatial and temporal resolution by preserving individual electron events. Running ReCoDe on a workstation we demonstrate on-the-fly reduction and compression of raw data streaming off a detector at 3 GB/s, for hours of uninterrupted data collection. The output was 100-fold smaller than the raw data and saved directly onto network-attached storage drives over a 10 GbE connection. We discuss calibration techniques that support electron detection and counting (e.g., estimate electron backscattering rates, false positive rates, and data compressibility), and novel data analysis methods enabled by ReCoDe (e.g., recalibration of data post acquisition, and accurate estimation of coincidence loss).

scholarly journals Time-resolved imaging refractometry of microbicidal films using quantitative phase microscopy

2011 ◽  
Vol 16 (12) ◽  
pp. 120510 ◽  
Author(s):  
Matthew T. Rinehart ◽  
Tyler K. Drake ◽  
Francisco E. Robles ◽  
Lisa C. Rohan ◽  
David Katz ◽  
...  
Keyword(s):  
Time Resolved ◽  
Quantitative Phase ◽  
Phase Microscopy ◽  
Quantitative Phase Microscopy ◽  
Time Resolved Imaging

scholarly journals Extension of the Scope of Anionic Phospholipid-Based Nanoformulation to Kaempferol and Indometacin

2021 ◽  
Vol 16 (3) ◽  
pp. 1934578X2110026
Author(s):  
Noriyuki Uchida ◽  
Masayoshi Yanagi ◽  
Kei Shimoda ◽  
Hiroki Hamada
Keyword(s):  
Phosphatidic Acid ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Dispersion Agent

In this work, resveratrol was dispersed with anionic phospholipids of 1,2-dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG), 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, and 1,2-distearoyl-sn-glycero-3-phosphoglycerol. Moreover, small-sized nanoparticles of kaempferol and indometacin were successfully prepared by using DPPG as a dispersion agent.

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