Xu, X.; Kim, R.; Hyun, H.; Shukla, R. d.; Jin, T.

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 the 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 Ga2 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 Ga2 in both GDP- and GTP-bound states, with preferential binding to activated Ga2, thereby sustaining membrane recruitment and locally attenuating signaling. Loss of C2GAP1 enhances G-protein activation, disrupts front-specific inhibition, and impairs rapid reorientation in dynamic gradients. These findings define a direct coupling between heterotrimeric G proteins a subunit and a RasGAP as a core adaptive module that calibrates gradient sensing across wide concentration ranges.