D2.345 - Conformations of HVEM engaged in its Trans and Cis interactions are caused by two kinds of post-translational folding

Interaction between B- and T-lymphocyte attenuator (BTLA) and Herpes Virus Entry Mediator (HVEM) is of critical importance in immune tolerance and immune responses. HVEM can bind BTLA on the same immune cell (in cis) or when they are on different cells (in trans). The cellular context in which HVEM engages BTLA determines whether the cellular response is activating or inhibitory. Both cis and trans interactions have the same binding interface, suggesting different conformations of HVEM upon cis and trans binding. In our previous study, we have modeled both cis and trans full-length structures of HVEM.  However, the study of the transfer between these two conformations has not been studied.

The KOSMOS approach (S. Seo and M.K. Kim, 2012) was used to consider the dynamics of the transfer between the cis and trans- conformations of HVEM.

An enormous energy barrier upon the transfer from cis to trans conformation was revealed, suggesting the formation of two HVEM populations already at the stage of posttranslational folding prior to interaction of HVEM with its cis and trans proteins-partners.

Based upon these results,  the existence of two different folding pathways with the participation of two different chaperones can be suggested. Thus, the conformations of  HVEM engaged in its Trans and Cis interactions are due to two different kinds of post-translational folding.