Molecular basis for the evolution of species-specific hemoglobin capture by pathogenic Staphylococcus

Jacob E. Choby; Hanna B. Buechi; Allison J. Farrand; Eric P. Skaar; Matthew F. Barber

The most abundant source of heme-iron in the mammalian host is hemoglobin, which mediates 42 oxygen transport within circulating erythrocytes. The predominant adult hemoglobin consists of a tetramer 43 containing two α-globin and two β-globin protein subunits, each of which binds a single heme molecule 44 signatures of positive selection. Because globin genes have been shown to undergo gene conversion 94 which can distort inferred phylogenetic relationships, all analyses were performed using both a well-95 supported species tree as well as gene trees generated using PhyML. All tests detected significant 96 evidence of positive selection acting on both α-and β-globin using both species and gene phylogenies 97 (Supplemental Data) . Multiple iterations repeatedly identified two sites in α-and β-globin exhibiting strong 98 signatures of positive selection ( Figure 1A) . It was immediately apparent that these rapidly-evolving sites 99 localized to similar regions of the α-and β-globin proteins, specifically the N-terminal A helix and the 100 hinge region between the E and F helices ( Figure 1B ). In fact, the two sites exhibiting signatures of 101 selection in the α-and β-globin A helices are at homologous positions. These parallel signatures of 102 selection between α-and β-globin could indicate that a similar selective pressure has driven this 103 divergence between primate species. To investigate whether bacterial heme scavenging receptors could 104 be one such pressure, rapidly evolving sites were mapped onto a recently solved co-crystal structure 105 between human hemoglobin and the IsdB protein from S. aureus. Notably, all four residues are localized 106 to the IsdB binding interface, in close proximity to the NEAT1 domain ( Figure 1C ). Together these findings 107 indicate that primate globins have undergone rapid divergence at specific sites proximal to the binding 108 interface with Gram-positive bacterial hemoglobin receptors. 109 110 111 All rights reserved. No reuse allowed without permission.