The Topology, in Model Membranes, of the Core Peptide Derived from the T‐Cell Receptor Transmembrane Domain

Abstract

The T-cell receptor-CD3 complex (TCR-CD3) serves a critical role in protecting organisms from infectious agents. The TCR is a heterodimer composed of α- and β-chains, which are responsible for antigen recognition. Within the transmembrane domain of the α-subunit, a region has been identified to be crucial for the assembly and function of the TCR. This region, termed core peptide (CP), consists of nine amino acids (GLRILLLKV), two of which are charged (lysine and arginine) and are crucial for the interaction with CD3. Earlier studies have shown that a synthetic peptide corresponding to the CP sequence can suppress the immune response in animal models of T-cell-mediated inflammation, by disrupting proper assembly of the TCR. As a step towards the understanding of the source of the CP activity, we focused on CP in egg phosphatidylcholine/cholesterol (9:1, mol/mol) model membranes and determined its secondary structure, oligomerization state, and orientation with respect to the membrane. To achieve this goal, 15-residue segments of TCRα, containing the CP, were synthesized and spin-labeled at different locations with a nitroxide derivative. Electron spin-echo envelope modulation spectroscopy was used to probe the position and orientation of the peptides within the membrane, and double electron-electron resonance measurements were used to probe its conformation and oligomerization state. We found that the peptide is predominantly helical in a membrane environment and tends to form oligomers (mostly dimers) that are parallel to the membrane plane.

Evolution of CPEB4 Dynamics Across its Liquid–Liquid Phase Separation Transition

“…The EPR line shape reports site specifically on the degree of averaging of anisotropic magnetic interactions via rotational diffusion with correlation times (τ c ) in the range of 10 –6 –10 –10 seconds and can resolve different coexisting populations with different τ c values . Accordingly, EPR spectroscopy has been extensively used to study the dynamics associated with membranes, , liquid crystals, micellar solutions, proteins , and LLPS in polymers , and proteins. − Fluorescence techniques are also very useful for studying dynamic and structural properties of proteins and provide information complementary to that obtained by EPR and NMR in terms of the time scales observed and the degree of structural resolution. In the context of LLPS FRAP (fluorescence beaching after photobleaching) has been very useful in determining the diffusion time in and out of the droplets .…”

A novel ligand-independent peptide inhibitor of TREM-1 suppresses tumor growth in human lung cancer xenografts and prolongs survival of mice with lipopolysaccharide-induced septic shock

“…Recently, we have successfully used the SCHOOL model to develop a novel, ligand-independent peptide inhibitor of GPVI and demonstrated its antithrombotic activity [53]. Intriguingly, as revealed recently [54–56], different viruses use SCHOOL-like mechanisms to modulate the host immune response mediated by TCR and other MIRRs. Viruses represent years of evolution and the efficiency and optimization that come along with it suggesting that this ligand-independent strategy of receptor inhibition can be effectively used for therapeutic purposes.…”

Profiling the repertoire of T-cell receptor beta-chain variable genes in peripheral blood lymphocytes from subjects who have recovered from acute hepatitis B virus infection

“…In addition, these phenomena may be associated with the structural and spatial configuration of the TCR CDR3, such that different CDR3 sequences may permit the recognition of the same epitope if their molecular spacings are structurally similar. 35 Currently, anti-HBV treatment with nucleoside analogs is used to reduce liver inflammation and to prevent the development of cirrhosis and liver cancer. The curative effect of these None, no skewed TRBV family was detected.…”