The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors

Abstract

The class A scavenger receptor (cA-SR) family is a group of five evolutionarily related innate immune receptors. The cA-SRs are known for their promiscuous ligand binding; as they have been shown to bind bacteria, such as Streptococcus pneumoniae and Escherichia coli, as well as different modified forms of low-density lipoprotein. Three of the five family members possess a scavenger receptor cysteine-rich (SRCR) domain while the remaining two receptors lack the domain. Previous work has suggested that the macrophage-associated receptor with collagenous structure (MARCO) shares a recent common ancestor with the non-SRCR-containing receptors; however, the origin of the SRCR domain within the cA-SRs remains unknown. We hypothesize that the SRCR domains of the cA-SRs have a common origin that predates teleost fish. Using the newly available sequence data from sea lamprey and ghost shark genome projects, we have shown that MARCO shares a common ancestor with the SRCR-containing proteins. In addition, we explored the evolutionary relationships within the SRCR domain by reconstructing the ancestral SRCR domains of the cA-SRs. We identified a motif that is highly conserved between the cA-SR SRCR domains and the ancestral SRCR domain that consist of WGTVCDD. We also show that the GRAEVYY motif, a functionally important motif within MARCO, is poorly conserved in the other cA-SRs and in the reconstructed ancestral domain. Further, we identified three sites within MARCO's SRCR domain, which are under positive selection. Two of these sites lie adjacent to the conserved WGTVCDD motif, and may indicate a potential biological function for these sites. Together, these findings indicate a common origin of the SRCR domain within the cA-SRs; however, different selective pressures between the proteins may have caused MARCOs SRCR domain to evolve to contain different functional motifs when compared to the other SRCR-containing cA-SRs.

Keywords: MARCO; SR-A; evolution; scavenger receptor; selection.

Figure 1

Domain structure of the five class A Scavenger Receptors based on the protein sequences obtained from the Homo sapiens genome. SCARA3 terminates at its collagenous domain while SCARA4 possesses a C-type Lectin domain. SCARA5, MARCO, and SR-A all possess a terminal SRCR domain. Colmedin is a transmembrane protein with a collagenous and olfactomedin domain found in Strongylocentrotus purpuratus, which has been included as an outgroup in this study.

Figure 2

Phylogeny of all five Class A Scavengers using colmedin as an outgroup. MARCO branches with SCARA5 and SR-A after rooting on this outgroup. Posterior probabilities for branches with <0.7 confidence are shown with open circles. See Table S1 in Supplementary Material for complete sequence list and accession numbers. Scale bar denotes number of substitutions per site. SCARA3 in sea lamprey (Petromyzon marinus) and SCARA3 in southern platyfish (Xiphophorus maculatus) are labeled as (A) and (B) that shows the sea lamprey sequence of SCARA5. These are shown due to their long-branching pattern. (C) shows the colmedin sequence.

Figure 3

Evolution of an EGRVEVYH motif within SCARA5 and MARCO’s RGRAEVYY motif among different taxa. Taxa groups shown include mammals, birds and reptiles, fish, ghost shark, and sea lamprey. The ancestral sequence predicted from FastML is shown as a weblogo. This SCARA5 motif is highly conserved across taxa but MARCO’s motif is less conserved outside of mammals.

Figure 4

Analysis of SCARA5’s WGTVCDD motif and MARCO’s WGTICDD motif within different taxa. Taxa groups shown include mammals, birds and reptiles, fish, ghost shark, and sea lamprey. The ancestral sequence predicted from FastML is shown. The WGTVCDD motif is conserved between the ancestral proteins and within both SCARA5 and MARCO except at the valine residue (site 4 in the motif).

Figure 5

Alignment of the SRCR domains studied for positive selection test in PAML. The GRAEVYY motif and WGTICDD motif, found in MARCO, are labeled. Stars denote positions 442, 452, and 477 as sites identified as under positive selection from PAML.