Molecular dynamic simulation (MDS) guided structural study on CD3 cytoplasmic tails to unravel conformational changes during TCR/CD3 triggering

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B693
Abstract ID: 4511

Presenting Author:
Liangyu Wang , Research Assistant Graduate Student at Univ. of Missouri Sch. of Med., Univ. of Missouri, Columbia

Abstract:

Challenges posed by the dynamic structure of CD3 cytoplasmic tails (CTs) limit understanding triggering of the T cell antigen receptor (TCR). A conserved proline rich sequence (PRS) in CD3ε CT, crucial for productive activation of T cell immune function, recruits the signaling adaptor Nck to the CD3 after TCR engagement with stimulatory antigens. Our group designed pull-down assay to capture antigen-binding induced conformational change on CD3 CTs. Empirical data support CD3ε CT conformational changes modulate PRS accessibility to binding partners such as Nck, as part of a structural dynamic mechanism that contributes to TCR/CD3 triggering. To better understand CD3 conformational changes induced by TCR engagement, we applied molecular dynamic simulation (MDS) to a structural model of full TCR/CD3 complex associated with crucial cholesterol molecules, embedded in a T cell-specific phospholipid bilayer. By comparing inactive TCR/CD3 complex to an activated status, MDS reveals roles of lipids and possible structural alteration of CD3 CTs, with analysis of potential Nck binding and immunoreceptor tyrosine-based activation motif (ITAM) Tyr positioning in resting state and activated TCR. Results from pull-down assays and MDS also indicate that mutations on TCR/CD3 constant domains may regulate T cell activation threshold by impairing or enhancing CD3 CTs conformational change. These studies could unravel relevant structural alteration during TCR/CD3 triggering.