Deadly Spiders & Scary Zombies - NOT a Halloween Story - A near atomic resolution glance into the CNS

Synapses are specialized junctions between neurons that transmit and compute information in the brain, connecting neurons into millions of neural circuits. The establishment, properties, and dynamics of synapses are governed by diverse trans-synaptic signaling molecules that communicate their signal via multifarious interactions with their synaptic partners. Mutations in genes encoding these molecules have been associated with diverse neuropsychiatric and neurodegenerative disorders and as such, many of those are targeted by therapeutic compounds. Over the past few decades, tremendous efforts have been made to structurally characterize the trans-synaptic signaling molecules as well as their interacting partners. Nevertheless, their low expression levels and high structural complexity has posed a great challenge to traditional structural methods, such as NMR and X-ray crystallography. Advances in single particle cryo-EM now allow the capture of such complexed macromolecular assemblies at great details, thus providing snapshots into these fascinating molecules in action. Here we report the near atomic resolution structures of two such synaptic components, the cannabinoid receptor 1 (CB₁R), and teneurin, two transmembrane receptors that are primarily expressed in neurons and are considered to mediate various functions in synapse formation and maintenance. The structures provide a high-resolution glance into the receptors’ architectures and supplement structural insights into the interaction with their inter- and intra- cellular partners. Our results highlight the promise of using cryo-EM as an alternative approach for studying challenging macromolecular machineries and provide a framework for elucidating their mechanisms of action that could in turn be used for the design of future therapeutics.