Transmembrane peptides used to investigate the homo-oligomeric interface and binding hotspot of latent membrane protein 1 |
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Authors: | Sammond Deanne W Joce Catherine Takeshita Ryan McQuate Sarah E Ghosh Nilanjan Martin Jennifer M Yin Hang |
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Institution: | Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA. |
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Abstract: | Epstein-Barr virus (EBV), a human γ-herpesvirus, establishes lifelong infection by targeting the adaptive immune system of the host through memory B cells. Although normally benign, EBV contributes to lymphoid malignancies and lymphoproliferative syndromes in immunocompromised individuals. The viral oncoprotein latent membrane protein 1 (LMP-1) is essential for B lymphocyte immortalization by EBV. The constitutive signaling activity of LMP-1 is dependent on homo-oligomerization of its six-spanning hydrophobic transmembrane domain (TMD). However, the mechanism driving LMP-1 intermolecular interaction is poorly understood. Here, we show that the fifth transmembrane helix (TM5) of LMP-1 strongly self-associates, forming a homotrimeric complex mediated by a polar residue embedded in the membrane, D150. Replacement of this aspartic acid residue with alanine disrupts TM5 self-association in detergent micelles and bacterial cell membranes. A full-length LMP-1 variant harboring the D150A substitution is deficient in NFκB activation, supporting the key role of the fifth transmembrane helix in constitutive activation of signaling by this oncoprotein. |
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Keywords: | membrane proteins NF‐kappa B peptide chemical synthesis protein–protein interactions CD40 Epstein‐Barr virus |
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