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Join Professor Khalid Salaita from Emory University for a Force Talk entitled 'DNA probes light the way for receptor mechanobiology'.
Cells are highly dynamic structures that are constantly converting chemical energy into mechanical work to pull and push on one another and on their surroundings. These pulls and pushes are mediated by tiny molecular forces at the scale of tens of piconewtons. For context, 7 pN applied a distance of 1 nm is ~1 kcal/mol. Nonetheless, these forces can have profound biochemical consequences. For example, the rapidly fluctuating forces between immune cells and their targets can drastically tune immune response and function. Despite the importance of such forces, there are limited methods to study forces at the molecular scale and particularly at the junction of living cells. I’ll focus this talk on the role of forces in the adaptive immune response, and specifically T cells response. T cells are triggered when the T-cell receptor (TCR) which is expressed on the plasma membrane encounters its antigenic ligand, the peptide-major histocompatibility complex (pMHC), on the surface of target cells. Because T cells are highly migratory and immune recognition occurs at a dynamic junction where the T cell physically touches the target cell, the TCR as well as its many co-receptors must experience some level of molecular force. Indeed, the elegant early work by Lang and Reinherz indicated an important role for mechanics in activating T cells. Hence, a long-standing question in the field is whether T cells transmit defined forces to the TCR and whether physical forces influence immune function. I will describe our approach to addressing this problem through the development of DNA-based probes to visualize and manipulate TCR-pMHC forces during T-cell activation. I will first detail how DNA probes are engineered to measure and manipulate the magnitude of TCR-pMHC forces with piconewton force resolution. I will show that naïve OT-1 (CD8+) T cells transmit 12–19 pN forces to the TCR-antigen complex within seconds of ligand binding and preceding initial calcium signaling. Next, I will describe our work using DNA “locking” to measure the lifetime of highly transient TCR forces and especially with single amino acid mutants of the pMHC (altered peptide ligands). Next we employ advanced photonic methods to measure the orientation of TCR-pMHC forces. These experiments aimed to test the hypothesis that the TCR is an anisotropic mechanosensor. Finally, I will show that T cells display a dampened and poorly specific response to antigen agonists when TCR forces are chemically abolished or physically “filtered” to a level below ∼12 pN using mechanically labile DNA tethers. Altogether, the data supports the hypothesis that the T cell receptor is a mechanosensor and the tools described in this talk maybe applied broadly to better understand the role of biophysical forces in receptor signaling.
Khalid Salaita is the Samuel Candler Dobbs Professor of Chemistry, and Director for Graduate Studies in the Chemistry Department at Emory University in Atlanta, Georgia (USA). Khalid grew up in Jordan and moved to the US in 1997 to pursue his undergraduate studies at Old Dominion University in Norfolk, Virginia (USA). He worked under the mentorship of Prof. Nancy Xu studying the spectroscopic properties of plasmonic nanoparticles. He then obtained his Ph.D. with Prof. Chad Mirkin at Northwestern University (Evanston, IL) in 2006. During that time, he focused on the area of materials chemistry and studied the electrochemical properties of organic adsorbates patterned onto gold films and developed massively parallel scanning probe lithography approaches. From 2006-2009, Khalid was a postdoctoral scholar with Prof. Jay T. Groves at the University of California at Berkeley (USA) where he trained in the area of biophysical chemistry and investigated the role of receptor clustering in modulating cell signaling. In 2009, Khalid started his own lab at Emory University, where he is currently investigating the use of nucleic acids as molecular force sensors, smart drugs, and synthetic motors. In recognition of his independent work, Khalid has received a number of awards, most notably: the Alfred P. Sloan Research Fellowship, the Camille-Dreyfus Teacher Scholar award, the National Science Foundation Early CAREER award, the Kavli Fellowship, and Merck Future Insight Prize. Khalid is currently the director of the Center on Probes for Molecular Mechanotechnology, and an Associate Editor of SmartMat. Khalid’s program has been supported by NSF, NIH, and DARPA.
How to join:
This event will take place online via Microsoft Teams.
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