An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1

BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N-terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin-producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation. This was accompanied by reduced hormone storage in the INS-1E cells. In Drosophila, disruption of the helix compromised growth regulation. By demonstrating size-dependent binding on insulin granules, our finding highlights the function of MCS for BAR domain proteins in a biological context distinct from their function, e.g., at the plasma membrane during endocytosis. [Display omitted] •ICA69, PICK1, and arfaptins have an amphipathic helix N-terminal to their BAR domains•The amphipathic helix directs curvature-sensitive binding of PICK1 to insulin granules•Disruption of the amphipathic helix compromises insulin storage and growth Herlo et al. identify amphipathic helices N-terminal to BAR domains in ICA69, PICK1, and arfaptins, which direct curvature-sensitive binding to liposomes and insulin granules during maturation. Disruption of this motif reduces membrane binding to curved, but not flat, membranes, leading to compromised insulin storage and growth deficiency in flies.