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 [1]. There are thousands of cases of Lyme disease reported each year, making it a prevalent disease in North America and Eurasia [2]. In order for B. burgdorferi to survive in its host, it evades the host's immune system through the use of complement regulator-acquiring surface proteins. One such protein responsible for a successful initial infection is Borrelia burgdorferi complement regulator-acquiring surface protein 1, or BbCRASP-1 [1]. Because BbCRASP-1 binds host complement regulators to the spirochete's outer surface, B. burgdorferi remains undetected within the host [1]. 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 [3]. Recently, it was found that BbCRASP-1 binds to several other proteins in the extra cellular matrix of a human cell.
FunctionFunction
BbCRASP-1 can be found on the outer layer of the Lyme disease spirochete and is essential for the infiltration of the spirochete into the host [1]. BbCRASP-1 provides resistance for the spirochete against the host's 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 proteins. Therefore, Factor H binds to BbCRASP-1, which is bound to the outer surface of the spirochete. Because there are multiple BbCRASP-1 proteins on the spirochete, the spirochete is coated with Factor H and effectively able to infiltrate the host and go undetected in the host's plasma[1].
Relation to the Extra Cellular MatrixRelation to the Extra Cellular Matrix
Recently it was found that BbCRASP-1 not only binds to FH and FHL-1 proteins, but it also binds to several other human ligands such as BMP-2 and Extra cellular matrix ligands Collagen I, Collagen III, Collagen IV, fibronectin, laminin, and plasminogen (Hallstrom et al. 2010). As a result of this new finding, BbCRASP-1 is said to advocate the bypassing of the complementary immune system in addition to the pathogenesis of Lyme disease. BbCRASP-1 facilitates binding of “Borrelia burgdoferi” to human cells and tissues, which helps spread the infection (Hallstrom et al. 2010).
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StructureStructure
In nature, BbCRASP-1 exists as a homodimer bound to the spirochete's surface [2]. Researchers confirmed this by viewing the presence of pieces of the dimer in solution [2]. 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.
Importance of the C-terminusImportance of the C-terminus
Sequences of high conservation in the C-terminal regions of the protein’s monomers, , were of interest as a potential binding site [2]. Previous studies showed that deletion of these sites caused a complete inability of BbCRASP-1 to bind FH and FHL-1 regulators [3]. 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 [2]. 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 [2]. 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 [2].
Other Potential Binding SitesOther Potential Binding Sites
Additional studies were done to investigate the FH and FHL-1 binding sites on the protein. As with previous research, areas of high conservation were investigated due to their relationship with upholding the structure and function of the protein [4]. Researchers examined highly conserved areas of amino acid sequences along the of the protein. They saw that the majority of these regions clustered on a highly-exposed region of the protein.
ReferencesReferences
- ↑ 1.0 1.1 1.2 1.3 1.4 Bykowski T, Woodman ME, Cooley AE, Brissette CA, Brade V, Wallich R, Kraiczy P, Stevenson B. Coordinated expression of Borrelia burgdorferi complement regulator-acquiring surface proteins during the Lyme disease spirochete's mammal-tick infection cycle. Infect Immun. 2007 Sep;75(9):4227-36. Epub 2007 Jun 11. PMID:17562769 doi:10.1128/IAI.00604-07
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Cordes FS, Roversi P, Kraiczy P, Simon MM, Brade V, Jahraus O, Wallis R, Skerka C, Zipfel PF, Wallich R, Lea SM. A novel fold for the factor H-binding protein BbCRASP-1 of Borrelia burgdorferi. Nat Struct Mol Biol. 2005 Mar;12(3):276-7. Epub 2005 Feb 13. PMID:15711564 doi:10.1038/nsmb902
- ↑ 3.0 3.1 Kraiczy P, Hellwage J, Skerka C, Becker H, Kirschfink M, Simon MM, Brade V, Zipfel PF, Wallich R. Complement resistance of Borrelia burgdorferi correlates with the expression of BbCRASP-1, a novel linear plasmid-encoded surface protein that interacts with human factor H and FHL-1 and is unrelated to Erp proteins. J Biol Chem. 2004 Jan 23;279(4):2421-9. Epub 2003 Nov 7. PMID:14607842 doi:10.1074/jbc.M308343200
- ↑ Cordes FS, Kraiczy P, Roversi P, Simon MM, Brade V, Jahraus O, Wallis R, Goodstadt L, Ponting CP, Skerka C, Zipfel PF, Wallich R, Lea SM. Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi. Int J Med Microbiol. 2006 May;296 Suppl 40:177-84. Epub 2006 Mar 10. PMID:16530476 doi:10.1016/j.ijmm.2006.01.011