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.

doi:10.64898/2026.04.11.717886

bioRxiv · 10.64898/2026.04.11.717886

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.

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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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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.. 2026-04-12. Molecular dissection of protein complexes isolated from sections of human brain. https://doi.org/10.64898/2026.04.11.717886

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