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


Hwang W. , Mallis R.J. , Lang M.J. , Reinherz E.L. . PNAS. 2020 ; 117(37). 21336-21345


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Each 𝛼𝛽αβT cell receptor (TCR) functions as a mechanosensor. The TCR is comprised of a clonotypic TCR𝛼𝛽αβ 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 TCR𝛼𝛽αβ 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 TCR𝛼𝛽αβ-pMHC complex and its variants under physiologic loads to identify this mechanism and any attendant TCR𝛼𝛽αβ domain allostery. The TCR𝛼𝛽αβ-pMHC interface is dynamically maintained by contacts with a spectrum of occupancies, introducing a level of control via relative motion between V𝛼α and V𝛽β variable domains containing the pMHC-binding complementarity-determining region (CDR) loops. Without adequate load, the interfacial contacts are unstable, whereas applying sufficient load suppresses V𝛼α-V𝛽β motion, stabilizing the interface. A second level of control is exerted by C𝛼α and C𝛽β constant domains, especially C𝛽β and its protruding FG-loop, that create mismatching interfaces among the four TCR𝛼𝛽 αβdomains and with a pMHC ligand. Applied load enhances fit through deformation of the TCR𝛼𝛽αβ molecule. Thus, the catch bond involves the entire TCR𝛼𝛽αβ 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 TCR𝛼𝛽αβ ectodomain is structurally conserved, the proposed mechanism can be universally adopted to operate under load during immune surveillance by diverse 𝛼𝛽αβTCRs constituting the T cell repertoire.