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. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 772-784, 2011.

Although membrane proteins account for approximately one third of all proteins encoded in the human genome, the functions and structures of their transmembrane domains are much less understood than the water-soluble regions. A major hurdle in studying these transmembrane domains is the lack of appropriate exogenous agents that can be used as specific probes. Despite the daunting challenges, major strides have recently been made in targeting the transmembrane domains of a variety of membrane proteins. High affinity and selectivity have been achieved in model biophysical systems, membranes of bacteria, and mammalian cells.

Ungefähr ein Drittel aller im menschlichen Genom codierten Proteine sind Membranproteine. Funktion und Struktur ihrer Transmembrandomänen sind weitaus weniger gut verstanden als die der wasserlöslichen Regionen. Die größte Hürde bei der Untersuchung dieser Domänen ist der Mangel an geeigneten exogenen Substanzen, die als spezifisch bindende Sonden eingesetzt werden könnten. Trotz dieser Schwierigkeiten ist es in jüngster Zeit mehrfach gelungen, die Transmembrandomänen verschiedener Membranproteine gezielt anzusteuern. In biophysikalischen Modellsystemen, bakteriellen Membranen und Säugerzellen konnten hohe Affinitäten und Selektivitäten erzielt werden.