Intrinsically disordered cytoplasmic tail in netrin receptor DCC binds the large ribosomal subunit to inhibit...

Transmembrane receptors in neurons act as transducers of extrinsic growth cues by regulating local protein synthesis of specific mRNAs to facilitate axon guidance. In the absence of cues, receptors tether and silence translation at the membrane, but little is known about this receptor-ribosome interaction. Here, we show the direct and specific interaction between the transmembrane receptor Deleted in Colorectal Cancer, DCC, and the 60S subunit that leads to translation inhibition in the absence of DCC's growth cue, netrin-1. We combined translation assays, equilibrium binding, and NMR spectroscopic approaches and identified the plasma membrane-proximal portion of DCC's cytoplasmic tail, specifically residues 1123 to 1158, bind the 60S subunit. We show that this region is unstructured, providing evidence for how the subunit is tethered at the membrane. Pinpointing the electrostatic interaction between DCC and the 60S subunit protein eL5/uL18 that leads to translational silencing, we propose a two-part binding interaction that facilitates this function. Our findings reveal how DCC directly regulates local translation, shedding light on the role of transmembrane receptors in controlling protein synthesis during axon guidance.