Cry toxins produced by the bacterium Bacillus thuringiensis are effective biological insecticides. Cadherin-like proteins have been reported as functional Cry1A toxin receptors in Lepidoptera. Here we present data that demonstrate that a coleopteran cadherin is a functional Cry3Aa toxin receptor. The Cry3Aa receptor cadherin was cloned from Tenebrio molitor larval midgut mRNA, and the predicted protein, TmCad1, has domain structure and a putative toxin binding region similar to those in lepidopteran cadherin B. thuringiensis receptors. A peptide containing the putative toxin binding region from TmCad1 bound specifically to Cry3Aa and promoted the formation of Cry3Aa toxin oligomers, proposed to be mediators of toxicity in lepidopterans. Injection of TmCad1-specific double-stranded RNA into T. molitor larvae resulted in knockdown of the TmCad1 transcript and conferred resistance to Cry3Aa toxicity. These data demonstrate the functional role of TmCad1 as a Cry3Aa receptor in T. molitor and reveal similarities between the mode of action of Cry toxins in Lepidoptera and Coleoptera.The mode of action of Bacillus thuringiensis insecticidal Cry toxins has been extensively studied in lepidopteran larvae (1). Our current understanding is that the major factors that contribute to Cry toxicity in insects include solubilization and activation of the crystalline toxin as well as interactions between toxin and midgut receptors. In lepidopterans, several insect midgut proteins have been proposed as Cry toxin receptors (2).Cry1A receptor functionality has been demonstrated for cadherin proteins from Bombyx mori (3, 4), Manduca sexta (5, 6), Ostrinia nubilalis (7), and Heliothis virescens (8). The specific toxin-binding region in lepidopteran cadherins has been localized proximal to the cell membrane insertion site (9 -11). Mutations in toxin binding motifs of lepidopteran cadherin genes are genetically linked to Cry1Ac resistance in H. virescens (12, 13), Helicoverpa armigera (14, 15), and Pectinophora gossypiella (9, 16).Interactions between Cry toxins and cadherin receptors and the implications for toxicity have been studied in Lepidoptera more extensively than in any other insect order (2). According to the model proposed by Bravo et al. (17), Cry toxin binding to cadherin is followed by toxin oligomerization. Toxin oligomers reportedly are intermediates required for effective pore formation and ultimately toxicity (18). A fragment of the BtR1 cadherin from M. sexta, corresponding to repeat 12 and containing a critical toxin-binding region, enhanced the activity of Cry1A toxins in Lepidoptera (19) by promoting toxin oligomerization (20). However, other studies in Lepidoptera have found that cadherin fragments can reduce Cry1A toxicity (11,21). An alternative model suggests that Cry toxin binding to cadherin receptors activates intracellular pathways leading to cell death (22). Notably, in both models, cadherin is a critical contact point for Cry toxins that is pivotal for intoxication.In contrast to the lepidopteran model, r...