The structure of metabotropic glutamate receptor 7 discloses the modulation mechanism of the synaptic adhesion protein ELFN1
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Brief description: ELFN1 interacts with the apical surface of mGlu7 and acts as a positive allosteric modulator by triggering a conformational change of the receptor. This enabled development of an ELFN1-derived peptide that regulates the activation of mGlu7.
Credit: HIGHER EDUCATION PRESS
Extracellular leucine-rich repeat and fibronectin type-III domain-containing protein 1 (ELFN1) is a synaptic adhesion protein, which regulates the precise positioning and physiological functions of metabotropic glutamate receptors (mGlus). Deficiency of the mGlu-ELFN1 interaction leads to severe pathological outcomes such as epilepsy and night blindness. However, the underlying mechanisms are largely unknown.
Recently, a research team led by Profs. WU Beili and ZHAO Qiang from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences solved the cryo-electronic microscopy structures of mGlu7 bound to the ELFN1 ectodomain in five conformations, which reveal molecular details of the recognition and modulation between this interaction pair. The mGlu7-ELFN1 binding is mediated through interactions between the N-terminal tip of ELFN1 and a cleft on the apex of the receptor formed by helix L and the loops at its N and C termini. Combined with functional data, these structures suggest that ELFN1 exerts a positive allosteric modulatory effect on mGlu7 activation by inducing an inter-subunit conformational rearrangement of the receptor. These findings disclose a critical modulation site in the extracellular domain of mGlu7, and led to development of an ELFN1-derived peptide that regulates the activation of mGlu7.
The regulation of presynaptic GPCRs by trans-synaptic adhesion molecules is a frontier in molecular neuroscience. This study provides an atomic-level snapshot of an mGlu modulated by an endogenous trans-synaptic partner, which is valuable for understanding the molecular basis for synapse formation and neurotransmitter release. This study not only extends our knowledge about the complex landscape of the functional modulation of class C G protein-coupled receptors, but also provides new clues for future drug design. The work entitled “Structural basis for the synaptic adhesion protein ELFN1-mediated modulation of mGlu7” was published on Protein & Cell.