Evolutionary tuning of TAM receptor–ligand interfaces highlights electrostatic features associated with regenerative phagocytic signaling

Efficient resolution of neuroinflammation and debris clearance are key determinants of successful central nervous system (CNS) regeneration. Regenerative vertebrates such as Danio rerio often show faster immune resolution and debris clearance than mammals, yet the molecular determinants underlying these differences remain incompletely understood. TAM receptor tyrosine kinases (Tyro3, Axl, and Mertk) and their ligands Gas6 and Protein S are central regulators of phagocytosis and immune resolution in the nervous system, but whether intrinsic structural properties of these receptor–ligand complexes contribute to regenerative efficiency has not been systematically explored. Here, we perform a comparative in silico analysis of TAM receptors and ligands from zebrafish, human, and mouse, integrating sequence evolution, high-confidence structural modeling, interface characterization, and electrostatic analysis. Despite substantial sequence divergence between mammals and zebrafish, ligand-binding domains retain strong structural conservation, supporting a conserved global mode of TAM–ligand engagement. At the interface level, zebrafish complexes exhibit enhanced electrostatic contributions and increased salt-bridge density, particularly in the Tyro3–Protein S interaction. Residue-resolved electrostatic analysis identifies clustered interface hotspots that are conserved in spatial organization and physicochemical function across species, despite evolutionary rewiring of individual contacts. Together, these findings suggest that TAM receptor–ligand interfaces are evolutionarily tuned through subtle electrostatic and geometric optimization rather than large-scale structural changes. This conserved yet adaptable electrostatic framework supports a mechanistic hypothesis in which conserved TAM receptor architecture permits species-specific electrostatic tuning of receptor–ligand interfaces, potentially contributing to differences in TAM-dependent phagocytic signaling efficiency across vertebrates