Chemotaxis enables eukaryotic cells to detect and migrate along extracellular chemoattractant gradients spanning several orders of magnitude. This remarkable dynamic range relies on adaptation, a process that allows cells to reset their signaling machinery while preserving sensitivity to incremental changes in stimulus intensity. Although numerous actin-dependent feedback mechanisms have been characterized, the molecular basis of adaptation within an actin-independent core gradient-sensing module remains poorly understood. Here, we identify the Ras GTPase-activating protein, C2GAP1, as a critical F-actin-independent effector of the heterotrimeric G protein, Gα2, in Dictyostelium discoideum. Using cytoskeleton-free gradient-sensing cells, quantitative imaging, biochemical assays, FRET-based G-protein activation measurements, and structural modeling, we demonstrate that C2GAP1 controls concentration-dependent adaptation during gradient sensing. Mechanistically, C2GAP1 directly associates with Gα2 in both GDP- and GTP-bound states, with preferential binding to activated Gα2, thereby sustaining membrane recruitment and locally attenuating Ras and downstream signaling. Loss of C2GAP1 enhances G-protein activation, disrupts local inhibition, and impairs rapid reorientation in dynamic gradients. These findings define a direct coupling between heterotrimeric G proteins and the RasGAP, C2GAP1, as a core adaptive module that enables gradient sensing across a wide concentration range.
Xu et al. (Thu,) studied this question.