Molecular dissection of protein complexes isolated from sections of human brain
El-Baba, T. J.; Lutomski, C. A.; Bennett, J. L.; Lawrence, S. A. S.; Burnap, S. A.; Butroid, F. I.; Ramsay, O. B.; Radzevicius, T.; Wu, D.; Song, H.; Chan, K. L.; Parise, L. F.; Parise, E.; Struwe, W. B.; Murrough, J. W.; Russo, S. B.; Robinson, C. V.
Show abstract
Molecular studies of brain receptors and transporters have typically relied on recombinant systems, limiting insight into their organization in native tissue. Here, we develop nanobody-based immunoprecipitation coupled with native mass spectrometry to interrogate endogenous protein assemblies from post-mortem mouse and human brain sections. We exemplify our approach by characterizing the synaptic proteins VGluT1 and mGluR2. From a single mouse brain, we discover mGluR2/3 heterodimers, alongside mGluR2 homodimers. Considering regions of human brain heterodimeric mGluR2/3 is highly abundant in the OFC and sgACC ([~]70% and 50%, respectively) and forms regional-specific interactions with additional synaptic proteins. In a modest cohort of biobanked human tissue, associated with depression and suicide, we find increased mGluR2/3 in the OFC. Consistent with this, mice exhibit similar associations between heterodimer levels and stress-susceptibility. Overall, our approach provides a direct means for establishing molecular-behavioural links at the level of receptor organization in brain.
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