scholarly journals ADAPs intrinsically disordered region is an actin sponge regulating T cell motility

2021 ◽  
Author(s):  
Nirdosh Dadwal ◽  
Janine Degen ◽  
Jana Sticht ◽  
Tarek Hilal ◽  
Tatjana Wegner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Self Assembly ◽  
Actin Polymerization ◽  
Intrinsically Disordered Proteins ◽  
Critical Concentration ◽  
Cell Receptor ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region

Intrinsically disordered proteins (IDPs) play a vital role in biological processes that rely on transient molecular compartmentation1. In T cells, the dynamic switching between migration and adhesion mandates a high degree of plasticity in the interplay of adhesion and signaling molecules with the actin cytoskeleton2,3. Here, we show that the N-terminal intrinsically disordered region (IDR) of adhesion- and degranulation-promoting adapter protein (ADAP) acts as a multipronged scaffold for G- and F-actin, thereby promoting actin polymerization and bundling. Positively charged motifs, along a sequence of at least 200 amino acids, interact with both longitudinal sides of G-actin in a promiscuous manner. These polymorphic interactions with ADAP become constrained to one side once F-actin is formed. Actin polymerization by ADAP acts in synergy with a capping protein but competes with cofilin. In T cells, ablation of ADAP impairs adhesion and migration with a time-dependent reduction of the F-actin content in response to chemokine or T cell receptor (TCR) engagement. Our data suggest that IDR-assisted molecular crowding of actin above the critical concentration defines a new mechanism to regulate cytoskeletal dynamics. The principle of IDRs serving as molecular sponges to facilitate regulated self-assembly of filament-forming proteins might be a general phenomenon.

scholarly journals Highly Efficient NMR Assignment of Intrinsically Disordered Proteins: Application to B- and T Cell Receptor Domains

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e62947 ◽  
Author(s):  
Linnéa Isaksson ◽  
Maxim Mayzel ◽  
Maria Saline ◽  
Anders Pedersen ◽  
Joakim Rosenlöw ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Nmr Assignment ◽  
Intrinsically Disordered Proteins ◽  
Cell Receptor ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Highly Efficient

scholarly journals Dynamic microtubules regulate cellular contractility during T-cell activation

2017 ◽  
Vol 114 (21) ◽  
pp. E4175-E4183 ◽  
Author(s):  
King Lam Hui ◽  
Arpita Upadhyaya
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Actin Polymerization ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Cell Receptor ◽  
Force Generation ◽  
Actin Dynamics ◽  
Bipolar Filament

T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell–substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.

scholarly journals Biphasic mechanosensitivity of T cell receptor-mediated spreading of lymphocytes

2019 ◽  
Vol 116 (13) ◽  
pp. 5908-5913 ◽  
Author(s):  
Astrid Wahl ◽  
Céline Dinet ◽  
Pierre Dillard ◽  
Aya Nassereddine ◽  
Pierre-Henri Puech ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cellular Response ◽  
Actin Polymerization ◽  
Cell Spreading ◽  
Cell Receptor ◽  
Substrate Stiffness ◽  
Bond Rupture ◽  
Immune Recognition

Mechanosensing by T cells through the T cell receptor (TCR) is at the heart of immune recognition. While the mechanobiology of the TCR at the molecular level is increasingly well documented, its link to cell-scale response is poorly understood. Here we explore T cell spreading response as a function of substrate rigidity and show that remarkably, depending on the surface receptors stimulated, the cellular response may be either biphasic or monotonous. When adhering solely via the TCR complex, T cells respond to environmental stiffness in an unusual fashion, attaining maximal spreading on an optimal substrate stiffness comparable to that of professional antigen-presenting cells. However, in the presence of additional ligands for the integrin LFA-1, this biphasic response is abrogated and the cell spreading increases monotonously with stiffness up to a saturation value. This ligand-specific mechanosensing is effected through an actin-polymerization–dependent mechanism. We construct a mesoscale semianalytical model based on force-dependent bond rupture and show that cell-scale biphasic or monotonous behavior emerges from molecular parameters. As the substrate stiffness is increased, there is a competition between increasing effective stiffness of the bonds, which leads to increased cell spreading and increasing bond breakage, which leads to decreased spreading. We hypothesize that the link between actin and the receptors (TCR or LFA-1), rather than the ligand/receptor linkage, is the site of this mechanosensing.

scholarly journals Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif

2017 ◽  
Vol 114 (9) ◽  
pp. E1641-E1650 ◽  
Author(s):  
Tomas Wald ◽  
Frantisek Spoutil ◽  
Adriana Osickova ◽  
Michaela Prochazkova ◽  
Oldrich Benada ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Self Assembly ◽  
Intrinsically Disordered Proteins ◽  
Organic Matrix ◽  
Matrix Proteins ◽  
Disordered Proteins ◽  
Order Structure ◽  
Type I ◽  
Intrinsically Disordered ◽  
Evolutionarily Conserved

The formation of mineralized tissues is governed by extracellular matrix proteins that assemble into a 3D organic matrix directing the deposition of hydroxyapatite. Although the formation of bones and dentin depends on the self-assembly of type I collagen via the Gly-X-Y motif, the molecular mechanism by which enamel matrix proteins (EMPs) assemble into the organic matrix remains poorly understood. Here we identified a Y/F-x-x-Y/L/F-x-Y/F motif, evolutionarily conserved from the first tetrapods to man, that is crucial for higher order structure self-assembly of the key intrinsically disordered EMPs, ameloblastin and amelogenin. Using targeted mutations in mice and high-resolution imaging, we show that impairment of ameloblastin self-assembly causes disorganization of the enamel organic matrix and yields enamel with disordered hydroxyapatite crystallites. These findings define a paradigm for the molecular mechanism by which the EMPs self-assemble into supramolecular structures and demonstrate that this process is crucial for organization of the organic matrix and formation of properly structured enamel.

scholarly journals Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

Life ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 144 ◽  
Author(s):  
Federica Scollo ◽  
Carmelo La Rosa
Keyword(s):  
Self Assembly ◽  
Protein Transport ◽  
Intrinsically Disordered Proteins ◽  
Interaction Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Disordered Proteins ◽  
Future Perspective ◽  
Main Role ◽  
Membrane Phospholipids ◽  
Intrinsically Disordered

Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.

scholarly journals Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity

2017 ◽  
Vol 9 (6) ◽  
pp. 509-515 ◽  
Author(s):  
Joseph R. Simon ◽  
Nick J. Carroll ◽  
Michael Rubinstein ◽  
Ashutosh Chilkoti ◽  
Gabriel P. López
Keyword(s):  
Self Assembly ◽  
Intrinsically Disordered Proteins ◽  
Low Complexity ◽  
Disordered Proteins ◽  
Intrinsically Disordered

scholarly journals Capture of plasma membrane fragments from target cells by trogocytosis requires signaling in T cells but not in B cells

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5621-5628 ◽  
Author(s):  
Anne Aucher ◽  
Eddy Magdeleine ◽  
Etienne Joly ◽  
Denis Hudrisier
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Cell Biology ◽  
Actin Polymerization ◽  
Cell Activation ◽  
Cell Receptor ◽  
Target Cells

Abstract Upon recognition of their respective cellular partners, T and B cells acquire their antigens by a process of membrane capture called trogocytosis. Here, we report that various inhibitors of actin polymerization or of kinases involved in intracellular signaling partially or fully inhibited trogocytosis by CD8+ and CD4+ T cells, whereas they had no effect on trogocytosis by B cells. Similarly, trogocytosis by T cells was inhibited at 4°C, whereas in B cells it was independent of temperature, indicating that trogocytosis by B cells does not rely on active processes. By contrast, most inhibitors we tested impaired both T-cell and B-cell activation. The differential effect of inhibitors on T-cell and B-cell trogocytosis was not due to the higher affinity of the B-cell receptor for its cognate antigen compared with the affinity of the T-cell receptor for its own antigen, but it correlated tightly with the abilities of T cells and B cells to form conjugates with their target cells in the presence of inhibitors. Trogocytosis thus has different requirements in different cell types. Moreover, the capture of membrane antigen by B cells is identified as a novel signaling-independent event of B-cell biology.

scholarly journals Dynamics of GCN4 facilitate DNA interaction: a model-free analysis of an intrinsically disordered region

2016 ◽  
Vol 18 (8) ◽  
pp. 5839-5849 ◽  
Author(s):  
Michelle L. Gill ◽  
R. Andrew Byrd ◽  
Arthur G. Palmer, III
Keyword(s):  
Signaling Pathways ◽  
Intrinsically Disordered Proteins ◽  
Dna Interaction ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Model Free ◽  
Intrinsically Disordered Region ◽  
Disordered Regions

Intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered regions (IDRs) are known to play important roles in regulatory and signaling pathways.

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