TCR-pMHC: Envisioning the specialized dynamics of the target 5-component complex

Murray, Joseph S.

doi:10.1038/s41423-022-00856-3

Cited by 3 publications

(9 citation statements)

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“…Because the comparative geometry showed that the CDR2-loop closest contact with its cognate MHC α-helix defines a range (between different TCR:pMHC structures) corresponding to an arc distance of the central cysteine rotating through exactly 45° [11]. As originally hypothesized [25], the rotations for both domains are in the counter-clockwise (cc) direction, because the two, conspicuous IP of the MHC α-helices face in opposite directions (e.g., easily seen in Fig. 2C).…”

Section: Resultsmentioning

confidence: 95%

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Murray

2023

Molecular Immunology

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Section: Resultsmentioning

confidence: 95%

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Murray

2023

Molecular Immunology

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Section: Resultsmentioning

confidence: 99%

“…Taken together, the suggestion that both Vα and Vβ began with ‘restriction’ in terms of mobility along both MHC-I α-helices is interesting regarding this dual IP model for human TCR V-domains interacting with both MHC-I and MHC-II [25, 29]. While the split into two helices was ostensibly ‘lost’ for MHC-I α-2, i.e., allowing variable positioning of Vα, it was apparently not lost in the MHC-II beta lineage; thus, human Vα positioning is highly consistent between TCR restricted to MHC-II.…”

Section: Discussionmentioning

confidence: 99%

“…The equation series used to calculate a particular V-domain torque (τ θ ) is shown in Figure 1B & D through Figure 4B & D, where the general equations are described below. Firstly, the basic parameters for each were measured from the appropriate PDB file in VMD (https://www.ks.uiuc.edu/) using fixed a.a. positions for each variable, as previously described [11,25]. Briefly, mass (M) was computed from the a.a. sequence of each V-domain starting at position-1 in the crystal structure through the F-G-R-G motif near the end of the 110 a.a. domain using the ExPASy ProtPram algorithm (https://web.expasy.org/).…”

Section: Estimation Of V-domain Torquementioning

confidence: 99%

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Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Murray¹

2023

Preprint

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Ligand recognition by the human α/β T-cell antigen receptor (TCR) heterodimer protein, unlike the surface immunoglobulin (sIg) B-cell receptor, is not governed by relative binding affinity. Its interaction with the peptide (p) plus major histocompatibility complex (MHC) protein (abbrev. pMHC) involves some different molecular mechanism linking pMHC binding to T-cell functions. Recent analytical geometry of TCR:pMHC-II solved crystallographic structures (n = 40) revealed that each variable (V)-domain is bound in similar, yet mathematically unique orientations to its target pMHC groove. The relative position of the central cysteine of each V-domain was examined by multivariable calculus in spherical coordinates, where a simple volume element (dV) was found to describe clonotypic geometry with pMHC-II. Here, the study was expanded to include TCR:pMHC-I structures, and to model a physical mechanism, specifically involving the two directionally opposed inclined planes (IP) manifest by the two major α-helices prominent in both MHC-I and MHC-II proteins. Calculations for rotational torque of each V-domain, together with acceleration up and down the slopes of both MHC α-helices, were used to estimate the time a given V-domain spends sliding down its cognate MHC IP. This V-domain rotation/sliding mechanism appears to be quantitatively unique for each target TCR:pMHC complex. However, there is a common dichotomy between the mobility of each V-domain with respect to the two classes of MHC proteins. In both TCR:pMHC-I and TCR:pMHC-II, one V-domain positions consistently between different structures, while the other V-domain shows position variability. Strikingly, which of the V-domains is consistent or variable are opposites between the two MHC classes. The implications for TCR selection in the thymus, and peripheral T-cell activation utilizing this quaternary dynamics information could have directed evolution of extant T-cell biology.

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“…The theory of kinetic proofreading is still considered to be suitable and provides a thorough understanding of the interaction kinetics [ 74 , 87 , 129 ]. However, the realization of the non-equilibrium process, and the need to use external energy to enhance the specificity and sensitivity of recognition, allow for a better understanding of the nature of this interaction, which is confirmed in advanced studies on living cells [ 76 , 90 , 130 ]. It is obvious that modern research devoted to the development of products with an artificial T-cell receptor should, along with the thermodynamic aspect, consider the kinetics and mechanics of the interaction of a synthetic receptor with an antigen, which will increase the specificity and efficiency of therapy.…”

Section: Discussionmentioning

confidence: 99%

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

Shevyrev

Tereshchenko

Sennikov

2022

IJMS

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The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.

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TCR-pMHC: Envisioning the specialized dynamics of the target 5-component complex

Cited by 3 publications

References 13 publications

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

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