Rebuttal from Michel Bouvier and Terence E. Hébert

摘要

Is the jury really out?: Arguments made by Nevin Lambert and Jonathan Javitch (2014) are not terribly distant from our own positions in that we agree additional work is necessary to settle the question of GPCR dimers in situ, but we believe that cell-based and in vitro data largely support the existence of class A GPCR oligomers (see also Ferre et al. 2014). They argue that GPCRs are less stable than other oligomeric membrane proteins such as ion channels. Given the conformational flexibility required to serve their distinct functions in the cell, this is likely to be an important structural feature of GPCRs in the context of allosteric machines dedicated to sensing the environment and translating signalling events into cellular actions requiring interactions with many distinct effectors. Multiple, weak interfaces allow for allostery and the requirements of distinct organizational designs as needed by the cell. This would be lost in attempts to purify receptors for structural studies and probably explains why dimers are not always seen in crystal structures. This transience may not be reflected in vivo where receptors and signalling partners are wired into larger metastable arrays. This could explain why so few conserved interfaces have been identified in GPCR dimers. Mono-meric receptors may signal when forced into proteoliposomes, but relevance to GPCR biology remains an open question.