The iron-regulated staphylococcal lipoproteins

Abstract

Lipoproteins fulfill diverse roles in antibiotic resistance, adhesion, protein secretion, signaling and sensing, and many also serve as the substrate binding protein (SBP) partner to ABC transporters for the acquisition of a diverse array of nutrients including peptides, sugars, and scarcely abundant metals. In the staphylococci, the iron-regulated SBPs are significantly upregulated during iron starvation and function to sequester and deliver iron into the bacterial cell, enabling staphylococci to circumvent iron restriction imposed by the host environment. Accordingly, this subset of lipoproteins has been implicated in staphylococcal pathogenesis and virulence. Lipoproteins also activate the host innate immune response, triggered through Toll-like receptor-2 (TLR2) and, notably, the iron-regulated subset of lipoproteins are particularly immunogenic. In this review, we discuss the iron-regulated staphylococcal lipoproteins with regard to their biogenesis, substrate specificity, and impact on the host innate immune response.

Keywords: Fur; Staphylococcus; TLR2; iron acquisition; iron-regulated; lipoproteins; substrate binding protein.

Figure 1

S. aureus Fur boxes, SirR/MntR box, and IRLP signal peptides. (A) Fur box sequences within the promoter/operator region of operons encoding the indicated S. aureus SBP-encoding gene and the SirR/MntR box located upstream of sitC/mntC. (B) Signal peptides for the indicated IRLPs, with the lipobox indicated by the box. Nucleotide and protein sequences are all derived from S. aureus COL.

Figure 2

Iron acquisition systems in S. aureus. (A) Siderophore-dependent iron uptake systems. (B) Siderophore-independent iron uptake systems. Each system is discussed in the text. The open reading frame accession number, based on S. aureus COL genome, for each of the IRLPs (blue) is indicated. The directionality indicated for each of the genes is as in the genome. The red star represents heme and the open star represents protoporphyrin IX. Hb, hemoglobin; Hp, haptoglobin.

Figure 3

Representative structure of cluster A SBPs, and structures of protein-bound Fe-SA and Fe-SB. (A) Representative ribbon diagram to highlight some of the key characteristics of the cluster A SBPs, including the helical spine (yellow) connecting the alpha/beta N-terminal (blue) and C-terminal (red) lobes that surround the binding pocket (green triangle), and the two conserved glutamic acid residues (black) that interact with the membrane permease. (B) Structure of iron-bound staphyloferrin A with coordinating residues from the S. aureus HtsA SBP (PDB 3LI2). (C) Structure of iron-bound staphyloferrin B with coordinating residues from the S. aureus SirA SBP (PDB 3MWF).