scholarly journals Multivalent Interactions between Molecular Components Involved in Clathrin Independent Endocytosis Drive Protein Phase Separation

2021 ◽  
Author(s):  
Samsuzzoha Mondal ◽  
Samuel Botterbusch ◽  
Karthik Narayan ◽  
Imania Powers ◽  
Jason Zheng ◽  
...  
Keyword(s):  
Phase Transition ◽  
Protein Assemblies ◽  
Intracellular Loop ◽  
Transmembrane Receptors ◽  
Phase Partitioning ◽  
Binding Partners ◽  
Endocytic Machinery ◽  
Multivalent Interactions ◽  
Regulate Protein ◽  
Molecular Components

Endocytosis of transmembrane receptors initiates via molecular interactions between the activated receptor and the endocytic machinery. A specific group of receptors, including the β1-adrenergic receptor (β1-AR), is internalized through a non-clathrin pathway known as Fast Endophilin Mediated Endocytosis (FEME). A key question is: how does the endocytic machinery assemble and how is it modulated by activated receptors during FEME. Here we show that endophilin, a major regulator of FEME, undergoes a phase transition into liquid-like condensates, which facilitates the formation of multi-protein assemblies by enabling the phase partitioning of endophilin binding proteins. The phase transition can be triggered by specific multivalent binding partners of endophilin in the FEME pathway such as the third intracellular loop (TIL) of the β1-AR, and the proline-rich-motifs of lamellipodin (LPD-PRMs). Other endocytic accessory proteins can either partition into, or target interfacial regions of, these condensate droplets. On the membrane, TIL promotes protein clustering in the presence of endophilin and LPD-PRMs. Our results demonstrate how the multivalent interactions between endophilin, LPD-PRMs and TIL regulate protein assembly formation on the membrane, providing mechanistic insights into the priming and initiation steps of FEME.

scholarly journals Post-translational modifications of EZH2 in cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhongwei Li ◽  
Minle Li ◽  
Diandian Wang ◽  
Pingfu Hou ◽  
Xintian Chen ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Binding Partners ◽  
Regulate Protein ◽  
Main Component

AbstractEnhancer of zeste homolog 2 (EZH2), as a main component of Polycomb Repressive Complex 2, catalyzes histone H3K27me3 to silence its target gene expression. EZH2 upregulation results in cancer development and poor prognosis of cancer patients. Post-translational modifications (PTMs) are important biological events in cancer progression. PTMs regulate protein conformation and diversity functions. Recently, mounting studies have demonstrated that EZH2 stability, histone methyltransferase activity, localization, and binding partners can be regulated by PTMs, including phosphorylation, O-GlcNAcylation, acetylation, methylation and ubiquitination. However, the detailed molecular mechanisms of the EZH2-PTMs and whether other types of PTMs occur in EZH2 remain largely unclear. This review presents an overview of different roles of EZH2 modification and EZH2-PTMs crosstalk during tumorigenesis and cancer metastasis. We also discussed the therapeutic potential of targeting EZH2 modifications for cancer therapy.

Regulation of cell migration by α4 and α9 integrins

2019 ◽  
Vol 476 (4) ◽  
pp. 705-718 ◽  
Author(s):  
Willow Hight-Warburton ◽  
Maddy Parsons
Keyword(s):  
Cell Migration ◽  
Expression Profiles ◽  
Focal Adhesions ◽  
Cell Types ◽  
Tissue Expression ◽  
Signalling Pathways ◽  
Adherent Cell ◽  
Transmembrane Receptors ◽  
Binding Partners ◽  
And Migration

Abstract Integrins are heterodimeric transmembrane receptors that play an essential role in enabling cells to sense and bind to extracellular ligands. Activation and clustering of integrins leads to the formation of focal adhesions at the plasma membrane that subsequently initiate signalling pathways to control a broad range of functional endpoints including cell migration, proliferation and survival. The α4 and α9 integrins form a small sub-family of receptors that share some specific ligands and binding partners. Although relatively poorly studied compared with other integrin family members, emerging evidence suggests that despite restricted cell and tissue expression profiles, these integrins play a key role in the regulation of signalling pathways controlling cytoskeletal remodelling and migration in both adherent and non-adherent cell types. This review summarises the known shared and specific roles for α4 and α9 integrins and highlights the importance of these receptors in controlling cell migration within both homeostatic and disease settings.

GPCR-interacting proteins (GIPs): nature and functions

2004 ◽  
Vol 32 (5) ◽  
pp. 851-855 ◽  
Author(s):  
J. Bockaert ◽  
G. Roussignol ◽  
C. Bécamel ◽  
S. Gavarini ◽  
L. Joubert ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Scaffolding Proteins ◽  
Interacting Proteins ◽  
Heterotrimeric G Proteins ◽  
Transmembrane Receptors ◽  
Binding Partners ◽  
Wide Range ◽  
Range Of Functions ◽  
Monomeric Proteins ◽  
G Protein Coupled

The simplistic idea that seven transmembrane receptors are single monomeric proteins that interact with heterotrimeric G-proteins after agonist binding is definitively out of date. Indeed, GPCRs (G-protein-coupled receptors) are part of multiprotein networks organized around scaffolding proteins. These GIPs (GPCR-interacting proteins) are either transmembrane or cytosolic proteins. Proteomic approaches can be used to get global pictures of these ‘receptosomes’. This approach allowed us to identify direct but also indirect binding partners of serotonin receptors. GIPs are involved in a wide range of functions including control of the targeting, trafficking and signalling of GPCRs. One of them, Shank, which is a secondary and tertiary partner of metabotropic and ionotropic glutamate receptors, respectively, can induce the formation of a whole functional glutamate ‘receptosome’ and the structure to which it is associated, the dendritic spine.

scholarly journals Mechanisms of JAK/STAT pathway negative regulation by the short coreceptor Eye Transformer/Latran

2016 ◽  
Vol 27 (3) ◽  
pp. 434-441 ◽  
Author(s):  
Katherine H. Fisher ◽  
Wojciech Stec ◽  
Stephen Brown ◽  
Martin P. Zeidler
Keyword(s):  
Intracellular Signaling ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Signaling Cascades ◽  
Dome A ◽  
Transmembrane Receptors ◽  
Binding Motifs ◽  
Endocytic Machinery ◽  
Multiple Receptor ◽  
Stat Pathway

Transmembrane receptors interact with extracellular ligands to transduce intracellular signaling cascades, modulate target gene expression, and regulate processes such as proliferation, apoptosis, differentiation, and homeostasis. As a consequence, aberrant signaling events often underlie human disease. Whereas the vertebrate JAK/STAT signaling cascade is transduced via multiple receptor combinations, the Drosophila pathway has only one full-length signaling receptor, Domeless (Dome), and a single negatively acting receptor, Eye Transformer/Latran (Et/Lat). Here we investigate the molecular mechanisms underlying Et/Lat activity. We demonstrate that Et/Lat negatively regulates the JAK/STAT pathway activity and can bind to Dome, thus reducing Dome:Dome homodimerization by creating signaling-incompetent Dome:Et/Lat heterodimers. Surprisingly, we find that Et/Lat is able to bind to both JAK and STAT92E but, despite the presence of putative cytokine-binding motifs, does not detectably interact with pathway ligands. We find that Et/Lat is trafficked through the endocytic machinery for lysosomal degradation but at a much slower rate than Dome, a difference that may enhance its ability to sequester Dome into signaling-incompetent complexes. Our data offer new insights into the molecular mechanism and regulation of Et/Lat in Drosophila that may inform our understanding of how short receptors function in other organisms.

A space-based perspective on cloud phase partitioning over the Southern Ocean

2020 ◽  
Author(s):  
Quentin Coopman ◽  
Corinna Hoose ◽  
Martin Stengel
Keyword(s):  
Phase Transition ◽  
Southern Ocean ◽  
Droplet Size ◽  
Cloud Droplet ◽  
Effective Radius ◽  
Mixed Phase ◽  
Cloud Droplets ◽  
Phase Partitioning ◽  
Cloud Properties ◽  
Ice Production

<p>Liquid cloud droplets freeze homogeneously at -40°C. For temperature between -40 and 0°C, clouds can be either liquid, ice, or mixed-phase. Several variables determine the cloud phase: droplet size, ice nuclei concentration, meteorological parameters, etc. But, parameters which trigger, enhance or inhibit the phase transition are still poorly understood and disagreements remain between theory and observations. The phase transition is nonetheless important to determine cloud effects on climate.</p><p>In the present study, we analyse satellite observations from the geostationary passive instrument SEVIRI. We used the CLAAS-2 dataset to retrieve cloud top microphysical and optical properties from 2005 to 2015 over the Southern Ocean.</p><p>Cloud objects that contain liquid and ice pixels are identified for cloud top temperatures within specific temperature ranges: between -30 and -20°C, between -20 and -8°C, and between -8 to 0°C. The distributions of different cloud properties for mixed-phase, liquid or ice clouds are compared. For example, preliminary results show that cloud ice fraction increases with the cloud droplet size for cloud top temperature between -8 and 0°C. Indeed, ice fractions greater than 0.8 are associated with a median cloud droplet effective radius of 7 micrometers whereas ice fractions less than 0.2 are associated with a median cloud droplet effective radius of 12 micrometers. We hypothesize that this result can be associated to a secondary ice production process (e.g., the Hallet-Mossop process is the splinter production associated with riming process for temperature between -8 and -3°C and it can increase the ice particle concentration by several orders of magnitude). In line with our results, the Hallet-Mossop process is more efficient with larger cloud droplets. The spatial distribution of liquid and ice pixels within the cloud objects is also studied to better understand the phase partitioning of mixed-phase clouds.</p>

scholarly journals Membrane phase separation drives organization at B cell receptor clusters

2021 ◽  
Author(s):  
Sarah A Shelby ◽  
Ivan Castello-Serrano ◽  
Kathleen Wisser ◽  
Ilya Levental ◽  
Sarah Veatch
Keyword(s):  
Phase Transition ◽  
Plasma Membrane ◽  
B Cell ◽  
Plasma Membranes ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Membrane Phase ◽  
Phase Partitioning ◽  
Receptor Clusters ◽  
In Cells

Isolated plasma membranes separate into two coexisting liquid phases with distinct lipid and protein compositions but live cell plasma membranes do not macroscopically phase separate, leading to questions of whether and how the membrane phase transition contributes to functional heterogeneity in cells. Using quantitative super resolution microscopy we show that B cell receptor signaling platforms are nanoscale domains that quantitatively enrich membrane probes based on probe phase partitioning in isolated plasma membrane vesicles. Phase partitioning in vesicles also predicts relative probe mobility and retention at receptor clusters. The convergence between measurements in live cells and isolated membranes establishes a clear role for the membrane phase transition as an organizing principle in cells. We propose that physical properties fundamental to the membrane phase transition give rise to a plasma membrane that is a highly responsive medium, capable of compartmentalizing cellular processes in response to diverse stimuli.

scholarly journals The Precipitation Imaging Package: Phase Partitioning Capabilities

2021 ◽  
Vol 13 (11) ◽  
pp. 2183
Author(s):  
Claire Pettersen ◽  
Larry F. Bliven ◽  
Mark S. Kulie ◽  
Norman B. Wood ◽  
Julia A. Shates ◽  
...  
Keyword(s):  
Phase Transition ◽  
Phase Identification ◽  
Near Surface ◽  
Surface Precipitation ◽  
Phase Partitioning ◽  
Thermodynamic Conditions ◽  
Lapse Rates ◽  
Precipitation Phase

Surface precipitation phase is a fundamental meteorological property with immense importance. Accurate classification of phase from satellite remotely sensed observations is difficult. This study demonstrates the ability of the Precipitation Imaging Package (PIP), a ground-based, in situ precipitation imager, to distinguish precipitation phase. The PIP precipitation phase identification capabilities are compared to observer records from the National Weather Service (NWS) office in Marquette, Michigan, as well as co-located observations from profiling and scanning radars, disdrometer data, and surface meteorological measurements. Examined are 13 events with at least one precipitation phase transition. The PIP-determined onsets and endings of the respective precipitation phase periods agree to within 15 min of NWS observer records for the vast majority of the events. Additionally, the PIP and NWS liquid water equivalent accumulations for 12 of the 13 events were within 10%. Co-located observations from scanning and profiling radars, as well as reanalysis-derived synoptic and thermodynamic conditions, support the accuracy of the precipitation phases identified by the PIP. PIP observations for the phase transition events are compared to output from a parameterization based on wet bulb and near-surface lapse rates to produce a probability of solid precipitation. The PIP phase identification and the parameterization output are consistent. This work highlights the ability of the PIP to properly characterize hydrometeor phase and provide dependable precipitation accumulations under complicated mixed-phase and rain and snow (or vice versa) transition events.

Formation of paired helical filaments in Alzheimer's disease

1984 ◽  
Vol 42 ◽  
pp. 302-303
Author(s):  
J. Metuzals ◽  
D. F. Clapin ◽  
V. Montpetit
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Frontal Lobe ◽  
Giant Axon ◽  
Paired Helical Filaments ◽  
Normal Brain ◽  
Protein Assemblies ◽  
Electron Microscopic ◽  
Helical Symmetry ◽  
Structural Levels

Information on the conformation of paired helical filaments (PHF) and the neurofilamentous (NF) network is essential for an understanding of the mechanisms involved in the formation of the primary lesions of Alzheimer's disease (AD): tangles and plaques. The structural and chemical relationships between the NF and the PHF have to be clarified in order to discover the etiological factors of this disease. We are investigating by stereo electron microscopic and biochemical techniques frontal lobe biopsies from patients with AD and squid giant axon preparations. The helical nature of the lesion in AD is related to pathological alterations of basic properties of the nervous system due to the helical symmetry that exists at all hierarchic structural levels in the normal brain. Because of this helical symmetry of NF protein assemblies and PHF, the employment of structure reconstruction techniques to determine the conformation, particularly the handedness of these structures, is most promising. Figs. 1-3 are frontal lobe biopsies.

Microstructure of laser-irradiated, conducting Kapton polyimide

1995 ◽  
Vol 53 ◽  
pp. 502-503
Author(s):  
D. L. Callahan ◽  
Z. Ball ◽  
H. M. Phillips ◽  
R. Sauerbrey
Keyword(s):  
Electron Microscopy ◽  
Phase Transition ◽  
Transmission Electron Microscopy ◽  
Cross Section ◽  
Film Surface ◽  
Cross Sectional ◽  
General Utility ◽  
Transmission Electron ◽  
Considerable Debate ◽  
Potential Applications

Ultraviolet laser-irradiation can be used to induce an insulator-to-conductor phase transition on the surface of Kapton polyimide. Such structures have potential applications as resistors or conductors for VLSI applications as well as general utility electrodes. Although the percolative nature of the phase transformation has been well-established, there has been little definitive work on the mechanism or extent of transformation. In particular, there has been considerable debate about whether or not the transition is primarily photothermal in nature, as we propose, or photochemical. In this study, cross-sectional optical microscopy and transmission electron microscopy are utilized to characterize the nature of microstructural changes associated with the laser-induced pyrolysis of polyimide.Laser-modified polyimide samples initially 12 μm thick were prepared in cross-section by standard ultramicrotomy. Resulting contraction in parallel to the film surface has led to distortions in apparent magnification. The scale bars shown are calibrated for the direction normal to the film surface only.

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