FAM3B PANDER and FAM3C ILEI represent a distinct class of signaling molecules with a non-cytokine-like fold.

The FAM3 superfamily is predicted to contain classical four-helix bundle cytokines, featuring a typical up-up-down-down fold. Two members of FAM3 have been extensively studied. FAM3B PANDER has been shown to regulate glucose homeostasis and β cell function, whereas the homologous FAM3C ILEI has been shown to be involved in epithelial-mesenchymal transition and cancer. Here, we present a three-dimensional structure of a FAM3 protein, murine PANDER. Contrary to previous suggestions, PANDER exhibits a globular β-β-α fold. The structure is composed of two antiparallel β sheets lined by three short helices packing to form a highly conserved water-filled cavity. The fold shares no relation to the predicted four-helix cytokines but is conserved throughout the FAM3 superfamily. The available biological data and the unexpected new fold indicate that FAM3 PANDER and ILEI could represent a new structural class of signaling molecules, with a different mode of action compared to the traditional four-helix bundle cytokines.