Complement Regulator-Acquiring Surface Protein
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IntroductionIntroduction
Lyme disease is caused by the spirochete Borrelia burgdorferi, and is transferred into vertebrate hosts by zoonotic vectors such as Ixodes ticks (Bykowski et al. 2007). There are thousands of cases of Lyme disease reported each year, making it a prevalent disease in North America and Eurasia (Cordes et al. 2005). In order for B. burgdorferi to survive in its host, it evades its immune system through the use of surface proteins. One of the proteins responsible for a successful initial infection is Borrelia burgdorferi complement regulator-acquiring surface protein 1, or BbCRASP-1 (....). Because BbCRASP-1 binds host complement regulators to the spirochete's outer surface, it remains undetected within the host (Bykowski et al. 2007). BbCRASP-1 specifically binds to complement Factor H (FH) and Factor H-like proteins (FHL-1), which are responsible for the host's immune response and detection of pathogens (Kraiczy et al. 2004). Recently, It was found that Bb-CRASp binds to several other protiens in the extra cellular matrix.
FunctionFunction
Bb CRASP-1 can be found on the outer layer of the Lyme disease spirochete and it is essential for the infiltration of the spirochete into the host (Bykowski 2007). BbCRASP-1 provides resistance for the spirochete against the hosts complementary immune system as well as spreading of the spirochete within the host.
Host Immune Response EvasionHost Immune Response Evasion
BbCRASP-1 has an affinity for factor H and Factor H like protiens. Therefore, Factor H binds to Bb-CRASP-1 which is bound to the outer surface of the spirochete. Because there are multiple BbCRASP-1's on the spirochete, the spirochete is covered in Factor H and effectively able to infiltrate the host and go undetected in the host's plasma(Bykowski 2007).
Relation to the Extra Cellular MatrixRelation to the Extra Cellular Matrix
More recently it was found that not only does Bb-CRASP bind to FH and FH like proteins, it also bind to several other human ligands such as BMP-2 and Extra cellular matrix ligands Collagen I, Collagen III, Collagen IV, fibronectin, laminin, and plasminogen ( 2010 hallstrom at al.). As a result of this new finding, Bb-CRASP is said to advocate not only the bypassing of the complementary immune system, but the pathogenesis of lyme disease by facilitating “borrelia burgdoferi” to bind to human cells and tissues which helps spread the infection (2010 Hallstrom at al).
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StructureStructure
Sequences of high conservation in the C-terminal regions of the protein’s monomers, , were of interest as a potential binding site (Cordes F et al. 2005). Previous studies showed that deletion of these sites caused a complete inability of BbCRASP-1 to bind FH and FHL-1 regulators (Kraiczy P et al. 2004). Scientists determined whether the role of the C-terminus region was in maintaining structure or directly functioning as a binding site by mutating in the C-terminus region of the dimer to aspartate (Cordes F et al. 2005). This new polar molecule disrupted the hydrophobic interactions in the core of the C-terminal region and caused the entire structure to aggregate as functionally inert mutants. Both the C-terminally truncated and mutated BbCRASP-1 proteins lost their ability to dimerize, inhibiting them from binding to their host’s regulatory factors. It was then concluded that the C-terminus is a structurally sensitive region rather than a direct binding site (Cordes 2005). The C-terminus aids in the stabilization of the dimer by holding the in place. The C-terminal of one monomer lies against the of the other and keeps the structure together (Cordes F et al. 2005).
In nature, BbCRASP-1 exists as a dimer. Researchers confirmed this by viewing the presence of pieces of the dimer in solution (Cordes et al. 2005). They viewed the results through analytical ultracentrifugation and saw that dimeric crystals formed. If its dimeric state is threatened, BbCRASP-1 would not be able to function.