No abstract

Key PointsA motif associated with the gp41 loop region of HIV interacts with the T-cell receptor complex and inactivates antigen-specific T cells.

Background: HIV utilizes its fusion peptide (FP) to both fuse and immunosuppress T-cells. Results: A conserved GxxxG-like motif within FP is critical for its function and structure. Conclusion: The GxxxG-like motif exerts its role via interaction with the transmembrane domain of TCR␣. Significance: We shed light on the molecular mechanism of FP immunosuppressant activity and on the molecular recognition within the membrane milieu.

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.

Background:Recently, an immunosuppressive motif was identified in the HIV-1 envelope glycoprotein complex. Results: Both D-and L-stereoisomers of the motif inhibit T-cell receptor activation and preferentially bind T-cells over B-cells. Conclusion: The motif immunomodulates T-cells through interactions occurring within the membrane milieu.Significance: This study provides new insights into the immunosuppressive activity of the envelope glycoprotein complex and the molecular recognition within the membrane.