The αβ TCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site

Abstract

Each αβT cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCRαβ ligand-binding heterodimer and the noncovalently associated CD3 signaling subunits. When bound by ligand, an antigenic peptide arrayed by a major histocompatibility complex molecule (pMHC), the TCRαβ has a longer bond lifetime under piconewton-level loads. The atomistic mechanism of this “catch bond” behavior is unknown. Here, we perform molecular dynamics simulation of a TCRαβ-pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCRαβ domain allostery. The TCRαβ-pMHC interface is dynamically maintained by contacts with a spectrum of occupancies, introducing a level of control via relative motion between Vα and Vβ variable domains containing the pMHC-binding complementarity-determining region (CDR) loops. Without adequate load, the interfacial contacts are unstable, whereas applying sufficient load suppresses Vα-Vβ motion, stabilizing the interface. A second level of control is exerted by Cα and Cβ constant domains, especially Cβ and its protruding FG-loop, that create mismatching interfaces among the four TCRαβ domains and with a pMHC ligand. Applied load enhances fit through deformation of the TCRαβ molecule. Thus, the catch bond involves the entire TCRαβ conformation, interdomain motion, and interfacial contact dynamics, collectively. This multilayered architecture of the machinery fosters fine-tuning of cellular response to load and pMHC recognition. Since the germline-derived TCRαβ ectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverse αβTCRs constituting the T cell repertoire.

A general chemical crosslinking strategy for structural analyses of weakly interacting proteins applied to preTCR–pMHC complexes

“…The NMR peaks of the Vβ domain were lost partly because of the paramagnetic relaxation enhancement [PRE, ( 29 )] in the proximity of the tagging site, and partly because of the chemical exchange due to the K b -t2 complex formation. The inherent conformational dynamics of the β chain subdomains Vβ and Cβ ( 32 , 33 ) lead to ensemble-averaged paramagnetic effects and contributed to the uncertainty of the homoΔχ-tensor; however, the overall correlation ( Fig. 9 , B and C ) offered a rational basis for evaluating the complex docking.…”

Affinity selection in germinal centers: Cautionary tales and new opportunities

“…It has been shown that some cell-receptor adhesion molecules can be in two different conformational states, the so-called bent and extended states, the second one being favored in receptor-ligand complexes submitted to a tensile force [48]. Also, recently it has been described that TCRs can display dynamic ectodomain allostery [8,49]. Analogously, it has been recently reported in both the heavy and light chains [52].…”

Somatic genetics of CDR3 control TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

“…Alternatively/historically, intrinsic TCR affinity (i.e., equilibrium and rate binding constants specified by the α/β TCR protein) has been used to explain both thymic TCR selection and peripheral TCR recognition [4,36,37]. Clearly TCR distinguish rare target (agonist) pMHC from thousands of nonagonist pMHC on the APC surface; and this is not mutually exclusive of whether or not a physical force (TCR loading) is an obligate component of TCR function [8,37]. In these and other regards, there is a stereochemical alternative to an affinity-limited binding reaction [25][26][27].…”

“…This paper seeks to understand two puzzles of the TCR-pMHC interaction, wherein a novel examination of the first can be used to re-examine the second in the context of existing evidence. Firstly, compared to antibodies and indeed other protein:protein binding reactions, TCRs display quite low (µM) binding affinities for pMHC ligands [6][7][8]. Nevertheless, like antibodies, TCRs have exquisite specificity, where single peptide or MHC a.a. changes can dictate T-cell reactivity or non-reactivity [9][10][11][12][13][14][15][16][17].…”