Phylogenetic and protein structure analyses provide insight into the evolution and diversification of the CD36 domain 'apex' among scavenger receptor class B proteins across Eukarya

Abstract

The cluster of differentiation 36 (CD36) domain defines the characteristic ectodomain associated with scavenger receptor class B (SR-B) proteins. In bilaterians, SR-Bs play critical roles in diverse biological processes including innate immunity functions such as pathogen recognition and apoptotic cell clearance, as well as metabolic sensing associated with fatty acid uptake and cholesterol transport. While previous studies suggest this protein family is ancient, SR-B diversity across Eukarya has not been robustly characterized. We analyzed SR-B homologs identified from the genomes and transcriptomes of 165 diverse eukaryotic species. The presence of highly conserved amino acid motifs across major eukaryotic supergroups supports the presence of a SR-B homolog in the last eukaryotic common ancestor (LECA). Our comparative analyses of SR-B protein structure identifies the retention of a canonical asymmetric beta barrel tertiary structure within the CD36 ectodomain across Eukarya. We also identify multiple instances of independent lineage-specific sequence expansions in the apex region of the CD36 ectodomain -- a region functionally associated with ligand-sensing. We hypothesize that a combination of both sequence expansion and structural variation in the CD36 apex region may reflect the evolution of SR-B ligand sensing specificity between diverse eukaryotic clades. Significance StatementSR-Bs are well-described in bilaterians, however the diversity and evolution of this ancient receptor protein family is poorly understood across Eukarya. Our analyses reveal a conserved beta barrel tertiary structure across eukaryotic SR-Bs that correlates with the presence of an intramolecular tunnel. In contrast, the putative ligand-sensing region associated with the apex of the protein can be highly divergent in both sequence and structure within and between taxa. Our data confirm the antiquity of the SR-B receptor protein family in Eukaryota and improve characterization of SR-B diversity outside of Metazoa. We hypothesize that eukaryotic SR-B diversity may be used as a model to explore receptor protein evolution driven by lineage-specific ligand specificity.