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The cytoplasmic amino-terminus of the Latent Membrane Protein-1 of Epstein-Barr Virus: relationship between transmembrane orientation and effector functions of the carboxy-terminus and transmembrane domain

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Abstract

The Latent Membrane Protein 1 (LMP-1) protein of Epstein-Barr virus (EBV) is localized in the plasma membrane of the infected cell. LMP-1 possesses a hydrophobic membrane spanning domain, and charged, intracellular amino- and carboxy-termini. Two models have been proposed for the contribution of the amino-terminus to LMP-1's function: (i) as an effector domain, interacting with cellular proteins, or (ii) as a structural domain dictating the correct orientation of transmembrane domains and thereby positioning LMP-1's critical effector domains (i.e. the carboxy-terminus). However, no studies to date have addressed directly the structural contributions of LMP-1's cytoplasmic amino-terminus to function. This study was designed to determine if LMP-1's cytoplasmic amino-terminus (N-terminus) encodes information required solely for maintenance of proper topological orientation. We have constructed LMP-1 chimeras in which the cytoplasmic N-terminus of LMP-1 is replaced with an unrelated domain of similar size and charge, but of different primary sequence. Retention of the charged amino-terminal (N-terminal) cytoplasmic domain and first predicted transmembrane domain was required for correct transmembrane topology. The absolute primary sequence of the cytoplasmic N-terminus was not critical for LMP-1's cytoskeletal association, turnover, plasma membrane patching, oligomerization, Tumor Necrosis Factor Receptor-associated factor (TRAF) binding, NF-κB activation, rodent cell transformation and cytostatic activity. Furthermore, our results point to the hydrophobic transmembrane domain, independent of the cytoplasmic domains, as the primary LMP-1 domain mediating oligomerization, patching and cytoskeletal association. The cytoplasmic amino-terminus provides the structural information whereby proper transmembrane orientation is achieved.

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Acknowledgements

The TRAF expression plasmid and anti-HA antibody HA-11 were generous gifts from Bill Sugden. The TK-lacZ reporter was the gift of Brad Olwin. This work was supported by NIH CA-64610 and AI-01537 grants to JM Martin.

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Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Box 347, Boulder, CO 80309, Colorado, USA

    William F Coffin III, Kimberly D Erickson, Marloes Hoedt-Miller & Jennifer M Martin

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  1. William F Coffin III
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  2. Kimberly D Erickson
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  3. Marloes Hoedt-Miller
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  4. Jennifer M Martin
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Correspondence to Jennifer M Martin.

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Coffin III, W., Erickson, K., Hoedt-Miller, M. et al. The cytoplasmic amino-terminus of the Latent Membrane Protein-1 of Epstein-Barr Virus: relationship between transmembrane orientation and effector functions of the carboxy-terminus and transmembrane domain. Oncogene 20, 5313–5330 (2001). https://doi.org/10.1038/sj.onc.1204689

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