TCR-pMHC: may the force be of you?

Murray, Joseph S.

doi:10.1038/s41423-021-00635-6

Cited by 2 publications

(3 citation statements)

References 14 publications

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“…While initial slip bonds could be envisioned to directly lead to variable dx/dy values estimated here for Vα on MHC-I α-2 helices and Vβ on MHC-II alpha α-helices, if a direct trajectory were in play (i.e., no sliding), it is curious that Vβ on MHC-I α-1 and Vα on MHC-II beta α-helices showed little variability in dx/dy values between different TCR (Table 2; Table 3 & Supplement I). Importantly, the physical chemistry of similar protein:protein binding, including with some sIg, does not indicate an enzymatic 'lock-and-key' mechanism [37][38][39]; nor, an 'induced-fit', per se [5,38,39]; rather, a common dynamic might be in play upon each pMHC encounter [11,24,25]. We can consider the initial binding position (which we can imagine) of a given V-domain (A) and its position at the apex of the MHC α-helix IP (B), which we can also imagine, as being in conformational equilibrium (ΔGc ‡ ).…”

Section: Dichotomy Of V-domain Positioning On Mhc-ii Versus Mhc-i Inc...mentioning

confidence: 99%

“…A dichotomy was revealed by the calculations of these dynamics for Vα versus Vβ binding pMHC-I versus pMHC-II ligands. As such, a novel path is put forward for understanding evolved T-cell functions; this theory entails prevailing evidence that relative TCR binding affinity is not the mechanism of TCR antigen specificity [11,16,17,20,24].…”

Section: Introductionmentioning

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

Murray

2023

Molecular Immunology

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Section: Dichotomy Of V-domain Positioning On Mhc-ii Versus Mhc-i Inc...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…A dichotomy was revealed by the calculations of these dynamics for Vα versus Vβ binding pMHC-I versus pMHC-II ligands. As such, a novel path forward is defined for understanding evolved T-cell functions; this theory entails with prevailing evidence that relative TCR binding affinity is not the mechanism of TCR antigen specificity [11,16,17,20,24].…”

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confidence: 99%

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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TCR-pMHC: may the force be of you?

Cited by 2 publications

References 14 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

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