Dheeraj Prakaash

University of Oxford | OX · Department of Biochemistry

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to...

Solute carrier spinster homolog 2 (SPNS2), one of only four known major facilitator superfamily (MFS) lysolipid transporters in humans, exports sphingosine-1-phosphate (S1P) across cell membranes. Here, we explore the synergistic effects of lipid binding and conformational dynamics on SPNS2's transport mechanism. Using mass spectrometry, we discove...

Lipopolysaccharide (LPS) is a complex glycolipid molecule that is the main lipidic component of the outer leaflet of the outer membrane of Gram-negative bacteria. It has very limited lateral motion compared to phospholipids, which are more ubiquitous in biological membranes, including in the inner leaflet of the outer membrane of Gram-negative bact...

OmpA, a predominant outer membrane (OM) protein in Escherichia coli , affects virulence, adhesion, and bacterial OM integrity. However, despite more than 50 y of research, the molecular basis for the role of OmpA has remained elusive. In this study, we demonstrate that OmpA organizes the OM protein lattice and mechanically connects it to the cell w...

The membrane-bound lymphocyte-specific protein-tyrosine kinase (Lck) triggers T cell antigen receptor signalling to initiate adaptive immune responses. Despite many structure–function studies, the mode of action of Lck and the potential role of plasma membrane lipids in regulating Lck’s activity remains elusive. Advances in molecular dynamics simul...

Lipopolysaccharide (LPS) is a complex glycolipid molecule that is the main lipidic component of the outer leaflet of the outer membrane of Gram-negative bacteria. It has very limited lateral motion compared to phospholipids, which are more ubiquitous in biological membranes, including in the inner leaflet of the outer membrane of Gram-negative bact...

Evidence from a range of experimental methods and molecular simulations has recently revealed that the outer membrane of E. coli is phase-separated; there are regions that are densely packed with proteins and other regions that contain mostly lipids (lipopolysaccharide in the upper leaflet and phospholipids in the inner leaflet). This being the cas...

Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count and hearing defects. SPNS2 also exports the S1P-mimicking FTY720-P (Fingolimod) and thereby is central to the pharmacokinetics of this drug when...

β Barrel outer membrane proteins (OMPs) cluster into supramolecular assemblies that give function to the outer membrane (OM) of Gram-negative bacteria. How such assemblies form is unknown. Here, through photoactivatable cross-linking into the Escherichia coli OM, coupled with simulations, and biochemical and biophysical analysis, we uncover the bas...

The T cell antigen receptor (TCR-CD3) is an octameric protein complex located in the T cell plasma membrane. It plays a vital role in our adaptive immune system by recognising a wide variety of antigenic peptides attached to major histocompatibility complexes (pMHCs). Upon binding with pMHCs, the TCR-CD3 transmits a signal to its unstructured cytop...

The membrane-bound lymphocyte-specific protein-tyrosine kinase (Lck) triggers T cell antigen receptor signalling to initiate adaptive immune responses. Despite many structure-function studies, the mode of action of Lck and the potential role of plasma membrane lipids in regulating Lck’s activity remains elusive. Advances in molecular dynamics simul...

The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and m...

‘Virtual Reality’ is one of the most applicable, impressive and recently uplifted technologies that has been implemented in numerous approaches already. In the light of structural biological studies, virtual reality technology enables immersive 3D visualization of molecular structures, interactions, mechanisms etc., and molecular modelling at the a...

Aquaporins (AQPs) are a sub-class of proteins originating from the class of Major Intrinsic Proteins (MIPs). They occur in functionally homotetrameric forms and are located at the transmembrane region of the cell membrane in both prokaryotes and eukaryotes. They are basically water conducting channels permeating water molecules in and out of the ce...

The virtue of immunity is a pivotal factor for the survival of every living organism. Host cells physically counteract the action of foreign bodies upon it through its various gimmicks. Inflammations, one of the most popular of them, induced by the innate immune system are considered imperative for the pathogenesis of autoimmune disorders and for t...