StudioG24SecL04Tpc5
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Red is the Variable Region, Yellow is the Invariable Region, and Green is the IR6 region *This representation as an isometric dimer of VlsE illustrates the only crystal structure available on the PDB site. |
VlsEVlsE
The causative agent of Lyme Disease, a multi-stage infection, is a family of spirochetes found in the guts of Ixodes ticks. The Variable Major Protein (VMP)-like sequence Expressed (VlsE) is the specific outer-surface lipoprotein that enables the spirochete to evade immune response through mechanisms of antigenic variation. In addition to inducing a strong immune response in the host, VlsE is useful in the serodiagnosis of Lyme disease.
Structural OverviewStructural Overview
VlsE is shown to be composed of four sub-units, each consisting of a variable domain flanked by two invariable domains (Liang). The variable domains themselves contain six variable regions (VR) interspersed amongst six invariable regions (IR). The IRs are embedded deep within the protein covered by alpha helical loops. They are shielded by the VRs.
Variable RegionVariable Region
The outer surface lipoprotein of Borrelia burgdorferi [1] uses antigenic variation via gene conversion to evade host immune response. Crystal structure of VlsE1, a recombinant variant protein of VlsE, reveals six that form loop structures that entirely cover the membrane distal end of the protein. Almost 50% of the variable region’s surface area is exposed on the surface of VlsE. There are three major areas of the membrane distal portion on the protein surface that undergo antigenic variation [2]. It is likely that amino acid mutations of these residues change conformation of the looped structures and therefore vary the epitopes [3] throughout each variable region. Immune systems are overwhelmed with an astronomical number of different antigens. The loop structures cover predominantly the α-helical invariant regions of the protein. It is speculated that the locations of these variable regions on the membrane distal end shield the conserved regions of VlsE from antibody interaction and thereby contribute to immune evasion.
InvariableInvariable
Invariable Region:
AntigenicityAntigenicity
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Function in Immune System EvasionFunction in Immune System Evasion
The contributions that VlsE brings to immune evasion of Lyme Disease in B. Burgderfori is based on the variability of said protein. The variable domain keeps the immune system guessing by constantly changing the their side chains. The variable region also protects the invariable region where antibodies generally target in order to help in phagocytosis. There in fact only three antibody chains that can bind to the most consistently active invariable region IR6. Even though the invariable regions take up most of the gene casette the variable region takes up a lot of the surface area. This variability is the reason why VlsE is located on membrane of the bacterium of Lyme disease.
Clinical ApplicationClinical Application
Although VlsE is able to evade immune response and maintain persistent infection through antigenic variation, a peptide associated with IR6 has been found to have seriodiagnostic properties in Lyme disease[1]. In a comparative study of human sera using recombinant antigens of B. Burgdorferi, the samples displayed 80% seropositivity when studied for IgG antibodies when examined by ELISAs[2] . It suggests that the invariable regions of VlsE may serve as useful universal probes for Lyme disease. The sera sampled by the study were from the archives in Connecticut of patients who resided in the United States[3]. However, Lyme disease is not exclusive to the United States therefore further analysis of VlsE reactivity with Lyme disease borreliosis from broad geographical regions is required[4].