scholarly journals Identification of the first structurally validated covalent ligands of the small GTPase RAB27A

2022 ◽  
Author(s):  
Mostafa Jamshidiha ◽  
Thomas Lanyon-Hogg ◽  
Charlotte L. Sutherell ◽  
Gregory B. Craven ◽  
Montse Tersa ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Small Gtpase ◽  
Covalent Ligands ◽  
The Way

A novel Rab27A construct enables elucidation of covalent ligand binding, paving the way for structure-guided approaches against this challenging target.

LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 1033-1036 ◽  
Author(s):  
Tatsuo Kinashi ◽  
Memet Aker ◽  
Maya Sokolovsky-Eisenberg ◽  
Valentin Grabovsky ◽  
Chisato Tanaka ◽  
...  
Keyword(s):  
Shear Flow ◽  
Ligand Binding ◽  
Phorbol Esters ◽  
Leukocyte Adhesion ◽  
Deficiency Syndrome ◽  
Small Gtpase ◽  
High Avidity ◽  
Integrin Activation ◽  
Leukocyte Adhesion Deficiency ◽  
Rap1 Activation

AbstractRecently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.1 We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it “LAD-III.” (Blood. 2004;103:1033-1036)

scholarly journals Clearing the way: The small GTPase RhoA and endomesodermal specification

2006 ◽  
Vol 295 (1) ◽  
pp. 411-412
Author(s):  
Wendy S. Beane ◽  
David R. McClay
Keyword(s):  
Small Gtpase ◽  
The Way

Self-sacrifice for in-group's history: A diachronic perspective

2018 ◽  
Vol 41 ◽  
Author(s):  
Maria Babińska ◽  
Michal Bilewicz
Keyword(s):  
Clinical Psychology ◽  
Historical Events ◽  
Emotional Events ◽  
Reciprocal Process ◽  
The Way

AbstractThe problem of extended fusion and identification can be approached from a diachronic perspective. Based on our own research, as well as findings from the fields of social, political, and clinical psychology, we argue that the way contemporary emotional events shape local fusion is similar to the way in which historical experiences shape extended fusion. We propose a reciprocal process in which historical events shape contemporary identities, whereas contemporary identities shape interpretations of past traumas.

What is the purpose of cognition?

2020 ◽  
Vol 43 ◽  
Author(s):  
Aba Szollosi ◽  
Ben R. Newell
Keyword(s):  
Infinite Number ◽  
Human Cognition ◽  
The Way

Abstract The purpose of human cognition depends on the problem people try to solve. Defining the purpose is difficult, because people seem capable of representing problems in an infinite number of ways. The way in which the function of cognition develops needs to be central to our theories.

Peculiarity Parameters

1976 ◽  
Vol 32 ◽  
pp. 233-254
Author(s):  
H. M. Maitzen
Keyword(s):  
Magnetic Field ◽  
Magnetic Fields ◽  
Theoretical Work ◽  
Observational Evidence ◽  
Rotator Model ◽  
Peculiar Behaviour ◽  
Field Spectrum ◽  
Oblique Rotator ◽  
Ap Stars ◽  
The Way

Ap stars are peculiar in many aspects. During this century astronomers have been trying to collect data about these and have found a confusing variety of peculiar behaviour even from star to star that Struve stated in 1942 that at least we know that these phenomena are not supernatural. A real push to start deeper theoretical work on Ap stars was given by an additional observational evidence, namely the discovery of magnetic fields on these stars by Babcock (1947). This originated the concept that magnetic fields are the cause for spectroscopic and photometric peculiarities. Great leaps for the astronomical mankind were the Oblique Rotator model by Stibbs (1950) and Deutsch (1954), which by the way provided mathematical tools for the later handling pulsar geometries, anti the discovery of phase coincidence of the extrema of magnetic field, spectrum and photometric variations (e.g. Jarzebowski, 1960).

The mensuration of interfaces

1992 ◽  
Vol 50 (1) ◽  
pp. 216-217
Author(s):  
W.M. Stobbs
Keyword(s):  
Electron Microscopy ◽  
50Th Anniversary ◽  
Numerical Data ◽  
Industrial Applications ◽  
Dynamical Theory ◽  
Large Strains ◽  
Reasonable Approach ◽  
Lattice Resolution ◽  
Analogue To Digital ◽  
The Way

I do not have access to the abstracts of the first meeting of EMSA but at this, the 50th Anniversary meeting of the Electron Microscopy Society of America, I have an excuse to consider the historical origins of the approaches we take to the use of electron microscopy for the characterisation of materials. I have myself been actively involved in the use of TEM for the characterisation of heterogeneities for little more than half of that period. My own view is that it was between the 3rd International Meeting at London, and the 1956 Stockholm meeting, the first of the European series , that the foundations of the approaches we now take to the characterisation of a material using the TEM were laid down. (This was 10 years before I took dynamical theory to be etched in stone.) It was at the 1956 meeting that Menter showed lattice resolution images of sodium faujasite and Hirsch, Home and Whelan showed images of dislocations in the XlVth session on “metallography and other industrial applications”. I have always incidentally been delighted by the way the latter authors misinterpreted astonishingly clear thickness fringes in a beaten (”) foil of Al as being contrast due to “large strains”, an error which they corrected with admirable rapidity as the theory developed. At the London meeting the research described covered a broad range of approaches, including many that are only now being rediscovered as worth further effort: however such is the power of “the image” to persuade that the above two papers set trends which influence, perhaps too strongly, the approaches we take now. Menter was clear that the way the planes in his image tended to be curved was associated with the imaging conditions rather than with lattice strains, and yet it now seems to be common practice to assume that the dots in an “atomic resolution image” can faithfully represent the variations in atomic spacing at a localised defect. Even when the more reasonable approach is taken of matching the image details with a computed simulation for an assumed model, the non-uniqueness of the interpreted fit seems to be rather rarely appreciated. Hirsch et al., on the other hand, made a point of using their images to get numerical data on characteristics of the specimen they examined, such as its dislocation density, which would not be expected to be influenced by uncertainties in the contrast. Nonetheless the trends were set with microscope manufacturers producing higher and higher resolution microscopes, while the blind faith of the users in the image produced as being a near directly interpretable representation of reality seems to have increased rather than been generally questioned. But if we want to test structural models we need numbers and it is the analogue to digital conversion of the information in the image which is required.

CarR, a MarR-family regulator from Corynebacterium glutamicum, modulated antibiotic and aromatic compound resistance

2019 ◽  
Vol 476 (21) ◽  
pp. 3141-3159 ◽  
Author(s):  
Meiru Si ◽  
Can Chen ◽  
Zengfan Wei ◽  
Zhijin Gong ◽  
GuiZhi Li ◽  
...  
Keyword(s):  
Stress Response ◽  
Ligand Binding ◽  
Corynebacterium Glutamicum ◽  
Conformational Changes ◽  
Cysteine Oxidation ◽  
Transcriptional Regulatory ◽  
Ligand Free ◽  
Redox Sensing

Abstract MarR (multiple antibiotic resistance regulator) proteins are a family of transcriptional regulators that is prevalent in Corynebacterium glutamicum. Understanding the physiological and biochemical function of MarR homologs in C. glutamicum has focused on cysteine oxidation-based redox-sensing and substrate metabolism-involving regulators. In this study, we characterized the stress-related ligand-binding functions of the C. glutamicum MarR-type regulator CarR (C. glutamicum antibiotic-responding regulator). We demonstrate that CarR negatively regulates the expression of the carR (ncgl2886)–uspA (ncgl2887) operon and the adjacent, oppositely oriented gene ncgl2885, encoding the hypothetical deacylase DecE. We also show that CarR directly activates transcription of the ncgl2882–ncgl2884 operon, encoding the peptidoglycan synthesis operon (PSO) located upstream of carR in the opposite orientation. The addition of stress-associated ligands such as penicillin and streptomycin induced carR, uspA, decE, and PSO expression in vivo, as well as attenuated binding of CarR to operator DNA in vitro. Importantly, stress response-induced up-regulation of carR, uspA, and PSO gene expression correlated with cell resistance to β-lactam antibiotics and aromatic compounds. Six highly conserved residues in CarR were found to strongly influence its ligand binding and transcriptional regulatory properties. Collectively, the results indicate that the ligand binding of CarR induces its dissociation from the carR–uspA promoter to derepress carR and uspA transcription. Ligand-free CarR also activates PSO expression, which in turn contributes to C. glutamicum stress resistance. The outcomes indicate that the stress response mechanism of CarR in C. glutamicum occurs via ligand-induced conformational changes to the protein, not via cysteine oxidation-based thiol modifications.

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