Abstract
T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 Å in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions.
Highlights
T-cells constitute our primary cellular defense against pathogenic challenge and play a major role in controlling neoplasms
Questions remain over whether these changes accurately reflect how T cell receptor (TCR) engage peptide major histocompatibility complexes (pMHCs), or whether these observations are biased because they rely on a static image of a highly flexible protein interface that could be further affected by crystal lattice contacts, crystal packing, and/or crystallization conditions
The TCR governs T-cell specificity by discriminating between self and foreign peptides presented by MHC molecules
Summary
T-cells constitute our primary cellular defense against pathogenic challenge and play a major role in controlling neoplasms. The key molecular interface that enables T-cells to sense these threats is mediated by the clonally expressed T cell receptor (TCR) that classically distinguishes between self and foreign peptides. These peptides are derived from processed intra- and extra-cellular proteins, presented by highly diverse major histocompatibility complexes (pMHCs) on the surface of most. It has been shown that the TCR can recognize lipid antigens and metabolites presented by the invariant MHC-like cluster of differentiation 1d and MHC class I-related molecules, respectively [4, 5]. Further evidence has implicated several other MHC-like molecules as antigenic targets for T-cells, exemplifying the extreme versatility of the TCR [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
