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

TL;DR

This study uses comparative in silico analysis to reveal that TAM receptor-ligand interfaces are evolutionarily optimized through electrostatic and geometric features, influencing regenerative phagocytic signaling across species.

Contribution

It uncovers conserved electrostatic and structural features in TAM receptor-ligand interfaces that differ among species, highlighting evolutionary tuning mechanisms.

Findings

Zebrafish complexes show enhanced electrostatic interactions.

Conserved structural engagement despite sequence divergence.

Electrostatic hotspots are spatially conserved across species.

Abstract

Efficient resolution of neuroinflammation and debris clearance is a key determinant of successful central nervous system regeneration. Regenerative vertebrates such as Danio rerio often exhibit 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 present 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, ligand-binding domains display strong structural conservation, supporting a conserved global mode of TAM-ligand engagement. At the interface level, zebrafish complexes show enhanced electrostatic contributions and increased salt-bridge density, particularly in the Tyro3-Protein S interaction. Residue-level electrostatic analysis reveals clustered interface hotspots that are spatially conserved across species despite evolutionary rewiring of individual contacts. Together, these results suggest that TAM receptor-ligand interfaces are evolutionarily tuned through subtle electrostatic and geometric optimization rather than large-scale structural changes, providing a conserved yet adaptable framework for species-specific modulation of phagocytic signaling.