Variability of the bacterial surface area disease and proteins appearance within a possible mouse style of systemic Lyme borreliosis. of spirochete membranes. Since Braun’s explanation Ranirestat of the lipoprotein (Lpp) in the cell envelope of (10), the key roles of lipoproteins in bacterial pathogenesis and physiology have already been increasingly appreciated. Lpp and various other prominent lipoproteins such as for example Pal are anchored in the internal leaflet from the external membrane, where they connect to peptidoglycan in the periplasm to stabilize the cell envelope (17). Research on lipoprotein export and adjustment have uncovered that Sec-dependent translocation is certainly accompanied by a three-step adjustment from the polypeptide in the periplasmic encounter of the inner membrane, resulting in a mature lipoprotein with an acylated amino-terminal cysteine anchor (42). In and likely other diderm (i.e., double membrane) bacteria (29), lipoprotein sorting and export to the outer membrane are determined by the identity of the penultimate N-terminal amino acid (37) and occur by the Lol pathway (37, 52, 53). Only a Plxnd1 few bacterial genera have actually been shown to deploy lipoproteins to their surface, and the mechanisms for this are largely unknown. The pullulanase PulA is transported to the outer surface through a complex type II secretion apparatus (42). Other characterized surface lipoproteins of bacterial pathogens include TbpB, which acts as part of a two-component transferrin receptor (2), the subtilisin-like protease SphB1 of (20), a potential adhesin of spp. (38). Lipoproteins are particularly abundant in the spirochetal genera (30). Several of them localize to the bacterial surface, i.e., the host-pathogen interface, and have thus received considerable attention as potential virulence determinants and vaccine targets. In spp., the agents of arthropod-borne Lyme borreliosis and relapsing fever (RF) (4), surface lipoproteins are important factors in pathogen transmission and persistence. For example, the Lyme borreliosis spirochete expresses outer surface protein OspA in the unfed tick; another lipoprotein, OspC, is upregulated during tick feeding and thought to be involved in tick-to-mammal transmission (28, 48). RF spirochetes such as repeatedly evade the host’s immune response by serial surface expression of immunodominant and antigenically variant lipoproteins, the variable small (Vsp) and large (Vlp) proteins (4). Two Vsps of are associated with niche selection; cells expressing Vsp2 (previously named VspB) grow to high densities in the blood, while those expressing Vsp1 (VspA) exhibit a neurotropic phenotype (14-16, 40). The structural features that underlie the biological functions of these and other borrelial surface lipoproteins have only Ranirestat begun to emerge. Our previous notion that RF Vsps and Vlps share primary and secondary structural features with Lyme borreliosis OspC and VlsE proteins (13, 54) was confirmed by X-ray crystallography. In contrast to OspA, which has a repetitive antiparallel beta topology (35), OspC (24, 33) and VlsE (23) are highly alpha-helical. Our recent Ranirestat determination of the Vsp1 structure showed that Vsps share a dimer four-helix bundle fold with OspC (C. L. Lawson, W. R. Zckert, and A. G. Barbour, unpublished data; 54). The observed variation between known Vsp alleles is predicted to occur mainly in the intervening loops and short beta-sheets distal to the bacterial outer membrane. We therefore concluded that the variation within these loops is likely responsible for the different biological functions of the paralogs belonging Ranirestat to this protein family (54). The structure-function analysis of Vsp and Vlp proteins has been hampered by the lack of a.