scholarly journals Computational Analysis of the Binding Specificities of PH Domains

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Zhi Jiang ◽  
Zhongjie Liang ◽  
Bairong Shen ◽  
Guang Hu
Keyword(s):  
Inositol Phosphates ◽  
Structural Aspect ◽  
Genomic Research ◽  
Ph Domain ◽  
Domain Structures ◽  
Ph Domains ◽  
Cellular Signal ◽  
Structure Relationship ◽  
Insight Into ◽  
Structure Properties

Pleckstrin homology (PH) domains share low sequence identities but extremely conserved structures. They have been found in many proteins for cellular signal-dependent membrane targeting by binding inositol phosphates to perform different physiological functions. In order to understand the sequence-structure relationship and binding specificities of PH domains, quantum mechanical (QM) calculations and sequence-based combined with structure-based binding analysis were employed in our research. In the structural aspect, the binding specificities were shown to correlate with the hydropathy characteristics of PH domains and electrostatic properties of the bound inositol phosphates. By comparing these structure properties with sequence-based profiles of physicochemical properties, PH domains can be classified into four functional subgroups according to their binding specificities and affinities to inositol phosphates. The method not only provides a simple and practical paradigm to predict binding specificities for functional genomic research but also gives new insight into the understanding of the basis of diseases with respect to PH domain structures.

scholarly journals Phosphotyrosine protein of molecular mass 30 kDa binds specifically to the positively charged region of the pleckstrin N-terminal pleckstrin homology domain

1999 ◽  
Vol 342 (2) ◽  
pp. 423-430
Author(s):  
Limin LIU ◽  
Mary MAKOWSKE
Keyword(s):  
Binding Site ◽  
Inositol Phosphates ◽  
Site Directed Mutagenesis ◽  
Pleckstrin Homology Domain ◽  
Ph Domain ◽  
Pleckstrin Homology ◽  
Glutathione S Transferase ◽  
Protein Protein Interaction ◽  
Ph Domains ◽  
Positively Charged

It has been proposed that phosphoinositides and inositol phosphates serve as general ligands for members of the structurally related pleckstrin homology (PH) domain family. The N-terminal PH domain of pleckstrin (N-PH), in contrast with other PH domains, does not bind to any of these ligands with the high affinity expected for a physiological interaction. To examine whether N-PH might instead mediate protein-protein interaction, a fusion protein with glutathione S-transferase (GST) expressing N-PH (GST-N-PH) was used to screen [35S]methionine metabolically labelled HL-60 and Bac1.2F5 cell lysates for potential binding partners. A 30 kDa binding protein was identified in both cell lines. Binding to N-PH demonstrated specificity, because binding was approx. 10-fold higher than when an equimolar amount of pleckstrin C-terminal PH domain (GST-C-PH) was used as probe. The 30 kDa protein could also be metabolically labelled with [32P]Pi and proved to be a tyrosine-phosphorylated protein. Binding to N-PH could be specifically inhibited with phosphotyrosine but not with phosphothreonine; the inhibition was concentration-dependent. Site-directed mutagenesis indicated that a positively charged region previously identified as the phosphoinositide-binding site in N-PH and other PH domains, rather than a putative phosphotyrosine-binding region previously identified in structurally similar phosphotyrosine-binding (PTB) domains, served as the binding site. These results suggest that the positively charged region of N-PH has the potential to interact with a protein ligand that contains phosphotyrosine.

The regulation of membrane to cytosol partitioning of signalling proteins by phosphoinositides and their soluble headgroups

2005 ◽  
Vol 33 (6) ◽  
pp. 1303-1307 ◽  
Author(s):  
C.P. Downes ◽  
A. Gray ◽  
A. Fairservice ◽  
S.T. Safrany ◽  
I.H. Batty ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Inositol Phosphates ◽  
Nucleotide Exchange ◽  
Ph Domain ◽  
Inositol Polyphosphates ◽  
Signalling Molecules ◽  
Nucleotide Exchange Factor ◽  
Inositol Phospholipids ◽  
Ph Domains ◽  
Pi Ligands

Inositol phospholipids [PIs (phosphoinositides)] represent a group of membrane-tethered signalling molecules which differ with respect to the number and distribution of monoester phosphate groups around the inositol ring. They function by binding to proteins which possess one of several domains that bind a particular PI species, often with high affinity and specificity. PH (pleckstrin homology) domains for example possess ligand-binding pockets that are often lined with positively charged residues and which bind PIs with varying degrees of specificity. Several PH domains bind not only PIs, but also their cognate headgroups, many of which occur naturally in cells as relatively abundant cytosolic inositol phosphates. The subcellular distributions of proteins possessing such PH domains are therefore determined by the relative levels of competing membrane-bound and soluble ligands. A classic example of the latter is the PH domain of phospholipase Cδ1, which binds both phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate. We have shown that the N-terminal PH domain of the Rho family guanine nucleotide-exchange factor, Tiam 1, binds PI ligands promiscuously allowing multiple modes of regulation. We also recently analysed the ligand-binding specificity of the PH domain of PI-dependent kinase 1 and found that it could bind abundant inositol polyphosphates such as inositol hexakisphosphate. This could explain the dual distribution of this key signalling component, which needs to access substrates at both the plasma membrane and in the cytosol.

Pleckstrin homology domains: not just for phosphoinositides

2004 ◽  
Vol 32 (5) ◽  
pp. 707-711 ◽  
Author(s):  
M.A. Lemmon
Keyword(s):  
Subcellular Localization ◽  
Human Genome ◽  
Small Gtpases ◽  
Membrane Targeting ◽  
Ph Domain ◽  
Cellular Membranes ◽  
Pleckstrin Homology ◽  
Ph Domains ◽  
Common Domain ◽  
Homology Domains

PH domains (pleckstrin homology domains) are the 11th most common domain in the human genome and are best known for their ability to target cellular membranes by binding specifically to phosphoinositides. Recent studies in yeast have shown that, in fact, this is a property of only a small fraction of the known PH domains. Most PH domains are not capable of independent membrane targeting, and those capable of doing so (approx. 33%) appear, most often, to require both phosphoinositide and non-phosphoinositide determinants for their subcellular localization. Several recent studies have suggested that small GTPases such as ARF family proteins play a role in defining PH domain localization. Some others have described a signalling role for PH domains in regulating small GTPases, although phosphoinositides may also play a role. These findings herald a change in our perspective of PH domain function, which will be significantly more diverse than previously supposed.

In Silico Insight into Nucleosome Repositioning Via Oxygen Delivery and Extracellular Movement

2021 ◽  
Author(s):  
Jacob Duane Madison
Keyword(s):  
In Silico ◽  
Binding Motif ◽  
Oxygen Intake ◽  
Ph Domain ◽  
Nutrient Delivery ◽  
Histone Octamer ◽  
Partial Pressures ◽  
Energy Dependent ◽  
Insight Into ◽  
Biomechanical Strain

Abstract OBJECTIVEHistones and resulting nucleosomes occur within DNA regulating gene expression by slowing, pausing, or halting transcriptional machinery. Positions within the genome have been found with higher affinity for the histone octamer than others. Histone/nucleosome repositioning is adjusted via energy dependent remodeling complexes, and a harmonizing array of constellation proteins and molecules. The energy required to create transcriptional environments is created through oxygen intake, nutrient presence, and extracellular movement. In this paper we aim to help facilitate an in silico framework for further experimentation into how partial pressures of oxygen and other gases impact genetic transcription along with extracellular movement and nutrient delivery.RESULTSCell and tissue culture experimentation with biomechanical strain and variable partial pressures of oxygen and other gases can be made into the expression levels of genes such as PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1), and Neuroligin 1 (NLGN1). These genes show in silico to have a higher affinity for a histone octamer binding motif, needing adequate cellular energy to be expressed. Extracellular movement and adequate cellular oxygenation are required to properly reposition nucleosome sequences for transcription.

The main reasons for substance formation and natural process manifestation

2021 ◽  
pp. 76-96
Author(s):  
Alexander Likhachev
Keyword(s):  
Thermodynamic Parameters ◽  
World History ◽  
Natural Process ◽  
Natural Materials ◽  
Main Factors ◽  
Composition Structure ◽  
The Impact ◽  
Insight Into ◽  
Structure Properties

Natural materials and processes represent the global substance reflecting and determining its formation and existence as a whole and in all its components. Revealing the reasons for their formation and manifestation is crucial. The paper highlights the two main factors: «influences» and «gradients». Influences are interpreted as the impact of some substances and events on other similar parameters, and gradients are vector changes and differences in systems composition, structure, properties, states, energy and thermodynamic parameters. To provide an insight into the role and significance of the above factors and reasons, an attempt was made to consider their potential manifestation throughout the general world history within the existing knowledge about it.

scholarly journals The PH Domain and the Polybasic c Domain of Cytohesin-1 Cooperate specifically in Plasma Membrane Association and Cellular Function

1998 ◽  
Vol 9 (8) ◽  
pp. 1981-1994 ◽  
Author(s):  
Wolfgang Nagel ◽  
Pierre Schilcher ◽  
Lutz Zeitlmann ◽  
Waldemar Kolanus
Keyword(s):  
Plasma Membrane ◽  
Cell Adhesion ◽  
Tyrosine Kinase ◽  
Biological Function ◽  
Common Mechanism ◽  
Membrane Association ◽  
Bruton’S Tyrosine Kinase ◽  
Ph Domain ◽  
Bruton's Tyrosine Kinase ◽  
Ph Domains

Recruitment of intracellular proteins to the plasma membrane is a commonly found requirement for the initiation of signal transduction events. The recently discovered pleckstrin homology (PH) domain, a structurally conserved element found in ∼100 signaling proteins, has been implicated in this function, because some PH domains have been described to be involved in plasma membrane association. Furthermore, several PH domains bind to the phosphoinositides phosphatidylinositol-(4,5)-bisphosphate and phosphatidylinositol-(3,4,5)-trisphosphate in vitro, however, mostly with low affinity. It is unclear how such weak interactions can be responsible for observed membrane binding in vivo as well as the resulting biological phenomena. Here, we investigate the structural and functional requirements for membrane association of cytohesin-1, a recently discovered regulatory protein of T cell adhesion. We demonstrate that both the PH domain and the adjacent carboxyl-terminal polybasic sequence of cytohesin-1 (c domain) are necessary for plasma membrane association and biological function, namely interference with Jurkat cell adhesion to intercellular adhesion molecule 1. Biosensor measurements revealed that phosphatidylinositol-(3,4,5)-trisphosphate binds to the PH domain and c domain together with high affinity (100 nM), whereas the isolated PH domain has a substantially lower affinity (2–3 μM). The cooperativity of both elements appears specific, because a chimeric protein, consisting of the c domain of cytohesin-1 and the PH domain of the β-adrenergic receptor kinase does not associate with membranes, nor does it inhibit adhesion. Moreover, replacement of the c domain of cytohesin-1 with a palmitoylation–isoprenylation motif partially restored the biological function, but the specific targeting to the plasma membrane was not retained. Thus we conclude that two elements of cytohesin-1, the PH domain and the c domain, are required and sufficient for membrane association. This appears to be a common mechanism for plasma membrane targeting of PH domains, because we observed a similar functional cooperativity of the PH domain of Bruton’s tyrosine kinase with the adjacent Bruton’s tyrosine kinase motif, a novel zinc-containing fold.

scholarly journals Mirco-level Insight into the Surface Tension-structure Relationship of Molten CaO–MgO–SiO2–FexO–P2O5 Slags

2021 ◽  
Vol 61 (11) ◽  
pp. 2765-2772
Author(s):  
Chengjun Liu ◽  
Rui Zhang ◽  
Yifan Meng ◽  
Zhen Wang ◽  
Shiyan Jiao ◽  
...  
Keyword(s):  
Surface Tension ◽  
Structure Relationship ◽  
Relationship Of ◽  
Insight Into ◽  
Tension Structure

scholarly journals Complementary roles of mechanotransduction and inflammation in vascular homeostasis

2021 ◽  
Vol 477 (2245) ◽  
pp. 20200622
Author(s):  
Marcos Latorre ◽  
Bart Spronck ◽  
Jay D. Humphrey
Keyword(s):  
Theoretical Model ◽  
Vascular Health ◽  
Induced Hypertension ◽  
Health And Disease ◽  
Vascular Geometry ◽  
Mechanical Homeostasis ◽  
Using Data ◽  
And Function ◽  
Insight Into ◽  
Structure Properties

Arteries are exposed to relentless pulsatile haemodynamic loads, but via mechanical homeostasis they tend to maintain near optimal structure, properties and function over long periods in maturity in health. Numerous insults can compromise such homeostatic tendencies, however, resulting in maladaptations or disease. Chronic inflammation can be counted among the detrimental insults experienced by arteries, yet inflammation can also play important homeostatic roles. In this paper, we present a new theoretical model of complementary mechanobiological and immunobiological control of vascular geometry and composition, and thus properties and function. We motivate and illustrate the model using data for aortic remodelling in a common mouse model of induced hypertension. Predictions match the available data well, noting a need for increased data for further parameter refinement. The overall approach and conclusions are general, however, and help to unify two previously disparate literatures, thus leading to deeper insight into the separate and overlapping roles of mechanobiology and immunobiology in vascular health and disease.

Magnetic State Switching in FeGa Microstructures

2021 ◽  
Author(s):  
MICHAEL GUEVARA DE JESUS ◽  
Zhuyun Xiao ◽  
Maite Goiriena-Goikoetxea ◽  
Rajesh V Chopdekar ◽  
Mohanchandra K Panduranga ◽  
...  
Keyword(s):  
Electric Field ◽  
Magnetic Circular Dichroism ◽  
Axial Strain ◽  
Vortex State ◽  
Magnetoelectric Composite ◽  
Domain Structures ◽  
Photoemission Electron ◽  
Insight Into ◽  
Electric Field Induced Strain

Abstract This work demonstrates that magnetoelectric composite heterostructures can be designed at the length scale of 10 microns that can be switched from a magnetized state to a vortex state, effectively switching the magnetization off, using electric field induced strain. This was accomplished using thin film magnetoelectric heterostructures of Fe81.4Ga18.6 on a single crystal (011) [Pb(Mg1/3Nb2/3)O3]0.68-[PbTiO3]0.32 (PMN-32PT) ferroelectric substrate. The heterostructures were tripped from a multi-domain magnetized state to a flux closure vortex state using voltage induced strain in a piezoelectric substrate. FeGa heterostructures were deposited on a Si-substrate for SQUID magnetometry characterization of the magnetic properties. The magnetoelectric coupling of a FeGa continuous film on PMN-32PT was characterized using a MOKE magnetometer with bi-axial strain gauges, and magnetic multi-domain heterostructures were imaged using X-Ray Magnetic Circular Dichroism – Photoemission Electron Microscopy (XMCD-PEEM) during the transition to the vortex state. The domain structures were modelled using MuMax3, a micromagnetics code, and compared with observations. The results provide considerable insight into designing magnetoelectric heterostructures that can be switched from an “on” state to an “off” state using electric field induced strain.

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