Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors

Habrian, Chris; Latorraca, Naomi; Fu, Zhu; Isacoff, Ehud Y.

doi:10.1038/s41467-023-44013-4

Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors

Journal Article · Tue Dec 12 23:00:00 EST 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-44013-4· OSTI ID:2470929

Habrian, Chris ^[1]; ^[2]; Fu, Zhu ^[2]; ^[3]

Stanford University School of Medicine, CA (United States); University of California, Berkeley, CA (United States)
University of California, Berkeley, CA (United States)
University of California, Berkeley, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Metabotropic glutamate receptors (mGluRs) are dimeric class C G-protein–coupled receptors that operate in glia and neurons. Glutamate affinity and efficacy vary greatly between the eight mGluRs. The molecular basis of this diversity is not understood. We used single-molecule fluorescence energy transfer to monitor the structural rearrangements of activation in the mGluR ligand binding domain (LBD). In saturating glutamate, group II homodimers fully occupy the activated LBD conformation (full efficacy) but homodimers of group III mGluRs do not. Strikingly, the reduced efficacy of Group III homodimers does not arise from differences in the glutamate binding pocket but, instead, from interactions within the extracellular dimerization interface that impede active state occupancy. By contrast, the functionally boosted mGluR II/III heterodimers lack these interface ‘brakes’ to activation and heterodimer asymmetry in the flexibility of a disulfide loop connecting LBDs greatly favors occupancy of the activated conformation. Our results suggest that dimerization interface interactions generate substantial functional diversity by differentially stabilizing the activated conformation. This diversity may optimize mGluR responsiveness for the distinct spatio-temporal profiles of synaptic versus extrasynaptic glutamate.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470929

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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