AI Article Synopsis
- LMP1 is a crucial protein from the Epstein-Barr virus (EBV), which infects a large portion of the global population and is associated with various cancers.
- The protein's activity relies on its oligomeric form, particularly the importance of its fifth transmembrane domain (TMD-5) and the critical residue D150, which is essential for activation and oligomerization.
- The study employs NMR techniques to explore the behavior of TMD-5 in micelles, revealing that D150's pKa is 7.4, influencing oligomer formations and showing that pentamidine can destabilize these structures while stabilizing lower-order forms.
Article Abstract
Latent membrane protein 1 (LMP1) is a gene product of the Epstein-Barr virus (EBV), a widely spread virus present in 90-95% of the world's population. EBV can lead to several malignancies, in which LMP1 was shown to play a key role. LMP1 is active only in the oligomeric form and its fifth transmembrane domain (TMD-5) is critical for the oligomerization, with D150 identified as a key residue for LMP1 activation. Here we propose an NMR-based approach to treat the complex oligomerization equilibria with slow conformational exchange. Using this method we investigate the TMD-5 in DPC micelles. We show that the pKa of D150 equals 7.4. Uncharged form of TMD-5 associates into dimers and trimers, deprotonation of D150 induces the high-order oligomerization of the protein and enhances dramatically its trimerization. Pentamidine interacts mainly with the charged TMD-5, destroying the oligomers and stabilizing the monomer and trimer. Using computer simulations we investigate the structural basis of TMD-5/pentamidine interaction. Our data suggest that D150 is likely charged in the full-length LMP1 under native conditions.
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| http://dx.doi.org/10.1016/j.bbamem.2020.183380 | DOI Listing |
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