Early studies of T cell structural biology using X-ray crystallography, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) focused on a picture of the αβT cell receptor (αβTCR) component domains and their cognate ligands (peptides bound to MHC molecules, i.e. pMHCs) as static interaction partners. Moving forward requires integrating this corpus of data with dynamic technologies such as NMR, molecular dynamics (MD) simulations and real-time single molecule (SM) studies exemplified by optical tweezers (OT). NMR bridges relevant timescales and provides the potential for an all-atom dynamic description of αβTCR components prior to and during interactions with binding partners. SM techniques have opened up vistas in understanding the non-equilibrium nature of T cell signaling through the introduction of force-mediated binding measurements into the paradigm for T cell function. In this regard, bioforces consequent to T-lineage cell motility are now perceived as placing piconewton (pN)-level loads on single receptor-pMHC bonds to impact structural change and αβT-lineage biology, including peptide discrimination, cellular activation, and developmental progression. We discuss herein essential NMR technologies in illuminating the role of ligand binding in the preT cell receptor (preTCR), the αβTCR developmental precursor, and convergence of NMR, SM and MD data in advancing our comprehension of T cell development. More broadly we review the central hypothesis that the αβTCR is a mechanosensor, fostered by breakthrough NMR-based structural insights. Collectively, elucidating dynamic aspects through the integrative use of NMR, SM, and MD shall advance fundamental appreciation of the mechanism of T cell signaling as well as inform translational efforts in αβTCR and chimeric T cell (CAR-T) immunotherapies and T cell vaccinology.
[ASAP] Identifying the Protein Interactions of the Cytosolic Iron–Sulfur Cluster Targeting Complex Essential for Its Assembly and Recognition of Apo-Targets
Identifying the Protein Interactions of the Cytosolic Iron–Sulfur Cluster Targeting Complex Essential for Its Assembly and Recognition of Apo-Targets
https://pubs.acs.org/appl/literatum/publisher/achs/journals/content/bichaw/0/bichaw.ahead-of-print/acs.biochem.7b00072/20180409/images/medium/bi-2017-00072x_0007.gif
Biochemistry
DOI: 10.1021/acs.biochem.7b00072
http://feeds.feedburner.com/~ff/acs/bichaw?d=yIl2AUoC8zA
http://feeds.feedburner.com/~r/acs/bichaw/~4/4KHGVmMLJ6o
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04-10-2018 12:35 AM
[NMR paper] Towards structural studies of self-assembled subviral particles: combining cell-free expression with 100 kHz MAS NMR.
Towards structural studies of self-assembled subviral particles: combining cell-free expression with 100 kHz MAS NMR.
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Angew Chem Int Ed Engl. 2018 Feb 19;:
Authors: David G, Fogeron ML, Schledorn M, Montserret R, Haselmann U, Penzel S, Badillo A, Lecoq L, André P, Nassal M, Bartenschlager R, Meier BH, Böckmann A
Abstract
Viral membrane proteins are prime targets in the combat against infection....
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02-21-2018 12:45 AM
[NMR paper] A bioresistant nitroxide spin label for in-cell EPR spectroscopy: in vitro and in oocytes protein structural dynamics studies.
A bioresistant nitroxide spin label for in-cell EPR spectroscopy: in vitro and in oocytes protein structural dynamics studies.
Approaching proteins structural dynamics and protein-protein interactions in the cellular environment is a fundamental challenge. Due to its absolute sensitivity and to its selectivity to paramagnetic species, Site-Directed Spin Labeling (SDSL) combined with Electron Paramagnetic Resonance (EPR) has the potential to evolve into an efficient method to follow conformational changes in proteins directly inside cells. Until now, the use of nitroxyde-based spin labels...
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12-12-2017 02:12 AM
[NMR paper] NMR-Directed Design of PreTCR? and pMHC Molecules Implies a Distinct Geometry for preTCR Relative to ??TCR Recognition of pMHC.
NMR-Directed Design of PreTCR? and pMHC Molecules Implies a Distinct Geometry for preTCR Relative to ??TCR Recognition of pMHC.
Related Articles NMR-Directed Design of PreTCR? and pMHC Molecules Implies a Distinct Geometry for preTCR Relative to ??TCR Recognition of pMHC.
J Biol Chem. 2017 Nov 03;:
Authors: Mallis RJ, Arthanari H, Lang MJ, Reinherz EL, Wagner G
Abstract
The pre-T cell receptor (preTCR) guides early thymocytes through maturation processes within the thymus via interaction with self ligands displayed on thymic...
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11-05-2017 04:56 PM
[NMR paper] A Unique Tool for Cellular Structural Biology: In-cell NMR.
A Unique Tool for Cellular Structural Biology: In-cell NMR.
Related Articles A Unique Tool for Cellular Structural Biology: In-cell NMR.
J Biol Chem. 2015 Dec 16;
Authors: Luchinat E, Banci L
Abstract
Conventional structural and chemical biology approaches are applied to macromolecules extrapolated from their native context. When doing so, important structural and functional features of macromolecules may be lost, which depend on their native network of interactions within the cell. In-cell nuclear magnetic resonance is a branch...
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12-28-2015 12:26 AM
[NMR paper] An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1 -antitrypsin upon ligand binding.
Protein Sci. 2015 May 26;
Authors: Nyon MP, Prentice T, Day J, Kirkpatrick J, Sivalingam GN, Levy G, Haq I, Irving JA, Lomas DA, Christodoulou J, Gooptu B, Thalassinos K
...
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05-27-2015 10:39 AM
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1-antitrypsin upon ligand binding
An integrative approach combining ion mobility mass spectrometry, X-ray crystallography and NMR spectroscopy to study the conformational dynamics of ?1-antitrypsin upon ligand binding
Abstract
Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whilst ion mobility (IM)-MS can report on conformational behaviour of specific states. We used IM-MS to study a conformationally labile protein (?1-antitrypsin) that undergoes pathological polymerisation in the context of point mutations. The folded, native state of the Z variant remains...
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05-26-2015 08:09 PM
[NMR paper] Towards an integrative structural biology approach: combining Cryo-TEM, X-ray crystallography, and NMR.
Towards an integrative structural biology approach: combining Cryo-TEM, X-ray crystallography, and NMR.
Related Articles Towards an integrative structural biology approach: combining Cryo-TEM, X-ray crystallography, and NMR.
J Struct Funct Genomics. 2014 Apr 20;
Authors: Lengyel J, Hnath E, Storms M, Wohlfarth T
Abstract
Cryo-transmission electron microscopy (Cryo-TEM) and particularly single particle analysis is rapidly becoming the premier method for determining the three-dimensional structure of protein complexes, and viruses....
NMR: an essential structural tool for integrative studies of T cell development, pMHC ligand recognition and TCR mechanobiology
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