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<Structure load='1w33' size='250' frame='true' align='right' caption='BbCRASP-1' scene='Insert optional scene name here' />
<StructureSection load='1w33' size='350' side='right' scene='SB2013_L01gr6/Bbcrasp-1_no_spacefill/2' caption='BbCRASP-1 (PDB code [[1w33]])'>
== '''Introduction'''  ==
 
[http://en.wikipedia.org/wiki/Lyme_disease Lyme Disease] is caused by the [http://en.wikipedia.org/wiki/Spirochaete spirochete] [http://en.wikipedia.org/wiki/Borrelia_burgdorferi  ''Borrelia burgdorferi''], and is transferred into vertebrate hosts by zoonotic vectors such as [http://en.wikipedia.org/wiki/Ixodes ''Ixodes''] ticks <ref name="Bykowski">PMID: 17562769</ref>. Lyme disease can result in multisystemic disorders, including cardiovascular and neurological problems. There are thousands of cases of Lyme disease reported each year, making it a prevalent disease in North America and Eurasia <ref name="Cordes">PMID: 15711564</ref>. 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''' <ref name="Bykowski">PMID: 17562769</ref>. Because BbCRASP-1 binds host complement regulators to the spirochete's outer surface, ''B. burgdorferi'' remains undetected within the host <ref name="Bykowski">PMID: 17562769</ref>. 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 <ref name="Kraiczy">PMID: 14607842</ref>. Recently, it was found that BbCRASP-1 binds to several other proteins in the extra cellular matrix of a human cell, making it highly flexible and adaptive.
 
*'''BbCRASP-2''' interacts preferentially with factor H<ref> PMID: 11385611</ref>.
*'''BbCRASP-3''' and  '''BbCRASP-4'''  belong to different strains of  ''Borrelia burgdorferi''<ref> PMID: 23219363</ref>.
== '''Structure''' ==
 
In nature, BbCRASP-1 exists as a homodimer bound to the spirochete's surface <ref name="Cordes">PMID: 15711564</ref>. BbCRASP-1 needs to be dimerized in order to bind FH/FHL-1 proteins. If its dimeric state is threatened, BbCRASP-1 would not be able to function.
 
=== '''Importance of the C-terminus''' ===
 
The C-terminus of BbCRASP-1 is a region crucial for its stability as a dimer. Previously,sequences of high conservation in the C-terminal regions of the protein’s monomers, <scene name='SB2013_L01gr6/C-terminus/1'>residues 241 to 250</scene> , were of interest as a potential binding site <ref name="Cordes">PMID: 15711564</ref>. Prior studies showed that deletion of these sites caused a complete inability of BbCRASP-1 to bind FH and FHL-1 regulators <ref name="Kraiczy">PMID: 14607842</ref>. The role of the C-terminus was determined by mutating <scene name='SB2013_L01gr6/Leucine_246/2'>leucine 246</scene> in this region of the dimer to aspartate <ref name="Cordes">PMID: 15711564</ref>. 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 <ref name="Cordes">PMID: 15711564</ref>. The C-terminus one monomer lies against the <scene name='SB2013_L01gr6/N-terminal_helix_ribbon/1'>N-terminal half of the E helix</scene> of the other and holds the <scene name='SB2013_L01gr6/Monomers_and_cterminus/1'>two monomers</scene> in place <ref name="Cordes">PMID: 15711564</ref>.


== '''Introduction''' ==
=== '''Other Potential Binding Sites''' ===


[http://en.wikipedia.org/wiki/Lyme_disease Lyme Disease] is caused by the [http://en.wikipedia.org/wiki/Spirochaete spirochete] [http://en.wikipedia.org/wiki/Borrelia_burgdorferi ''Borrelia burgdorferi''], and is transferred into vertebrate hosts by zoonotic vectors such as [http://en.wikipedia.org/wiki/Ixodes ''Ixodes''] ticks <ref name="Bykowski">PMID: 17562769</ref>. Lyme disease can result in multisystemic disorders, including cardiovascular and neurological problems. There are thousands of cases of Lyme disease reported each year, making it a prevalent disease in North America and Eurasia <ref name="Cordes">PMID: 15711564</ref>. 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 <ref name="Bykowski">PMID: 17562769</ref>. Because BbCRASP-1 binds host complement regulators to the spirochete's outer surface, ''B. burgdorferi'' remains undetected within the host <ref name="Bykowski">PMID: 17562769</ref>. 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 <ref name="Kraiczy">PMID: 14607842</ref>. Recently, it was found that BbCRASP-1 binds to several other proteins in the extra cellular matrix of a human cell, making it highly flexible and adaptive.
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 <ref name="CordesF">PMID: 16530476</ref>. Highly conserved areas of amino acid sequences among Borrelia CRASP-1 proteins encoded by the same gene were examined. The greatest homologous region was clustered on the <scene name='SB2013_L01gr6/Pocket_region_with_blue_fill/1'>center of the cleft region</scene> of the protein. A binding site in this region would be probable because this area allows more contact with the regulator proteins and would aid in further evasion of the immune system by shielding the binding domain from potential detection <ref name="CordesF">PMID: 16530476</ref>.


== '''Function''' ==
== '''Function''' ==
Line 15: Line 28:
=== '''Relation to the Extra Cellular Matrix''' ===
=== '''Relation 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 [http://www.uniprot.org/uniprot/BMP2_HUMAN BMP-2] and Extra cellular matrix ligands Collagen I, Collagen III, Collagen IV, fibronectin, laminin, and plasminogen <ref name"Hallstrom">PMID: 20565259</ref>. As a result of this new  finding, BbCRASP-1 is said to not only advocate the bypassing of the complementary immune system, but facilitate the dissemination of ''B. burgdorferi'' within the host's tissues <ref name"Hallström">PMID: 20565259</ref>. Binding to the ECM of a host is common strategy used by pathogens to acquire contact within the host  <ref name"Burgmann">PMID: 19118218</ref><ref name"Hallström">PMID: 16785539</ref>.  
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 [http://www.uniprot.org/uniprot/BMP2_HUMAN BMP-2] and Extra cellular matrix ligands Collagen I, Collagen III, Collagen IV, fibronectin, laminin, and plasminogen <ref name"Hallstrom">PMID: 20565259</ref>. As a result of this new  finding, BbCRASP-1 is said to not only advocate the bypassing of the complementary immune system, but facilitate the dissemination of ''B. burgdorferi'' within the host's tissues <ref name"Hallström">PMID: 20565259</ref>. Binding to the ECM of a host is common strategy used by pathogens to acquire contact within the host  <ref name"Burgmann">PMID: 19118218</ref><ref name"Hallström">PMID: 16785539</ref>.


== '''Discussion''' ==


<applet load='BBCRASP-12' size='250' frame='true' align='right' caption='BbCRASP-1' scene='Insert optional scene name here' />
In order for ''B. burgdorferi'' to successfully colonize its new and hostile environment, it depends on a complement of proteins to fend off the host’s immune system. BbCRASP-1 is extremely important as it serves as a “frontier” protein, helping to bring upon successful initial infection to which depends the entire course of the pathogen’s life cycle and existence within the host. As such it remains a protein of high interest to medical researchers who can use this valuable information to stem the tide of the colonization process before it develops into a full case of Lyme disease. BbCRASP-1’s high affinity for FH and FHL-1 complement factors and other ligands such as BMP-2, Collagen I, Collagen III, Collagen
IV, fibronectin, laminin, and plasminogen make it a highly flexible and adaptive protein well suited to aiding the pathogen in colonization.


== '''Structure''' ==
=== '''Future Studies''' ===
 
Further work needs to be done to determine the complement regulator protein and human ligand binding sites on BbCRASP-1. Knowing this information would aid in combating Lyme disease because it would give researchers a definite target for inhibitory drugs. However, with what is known about the protein, drugs that interfere with the C-terminus region of the dimer would also aid in mediating the effects of the disease because once the dimeric state of the protein is disrupted, it cannot function. These methods should also be applied to other CRASPs so FH/FHL-1 binding would be suppressed and the host's immune system can mount an effective defense against the invading spirochete.
</StructureSection>
== '''3D structure of BbCRASP''' ==
 
Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*CRASP-1 or Spa
 
**[[1w33]], [[1w3z]], [[4bl4]], [[5a2u]] - BbCRASP-1 extracellular domain - ''Borrelia burgdorferi''<br />


In nature, BbCRASP-1 exists as a homodimer bound to the spirochete's surface <ref name="Cordes">PMID: 15711564</ref>. BbCRASP-1 needs to be dimerized in order to bind FH/FHL-1 proteins. If its dimeric state is threatened, BbCRASP-1 would not be able to function.
*CRASP-2 or CspZ


=== '''Importance of the C-terminus''' ===
**[[4bg0]] – BbCRASP-2 residues 23-236<br />
**[[4cbe]] – BbCRASP-2 residues 23-236<br />
**[[6atg]], [[9f7i]] – BbCRASP-2 residues 23-236 + complement factor H<br />
**[[5y4m]] – BbCRASP-2 DISK domain residues 35-181 <br />


The C-terminus of BbCRASP-1 is a region crucial for its stability as a dimer. Previously,sequences of high conservation in the C-terminal regions of the protein’s monomers, <scene name='SB2013_L01gr6/C-terminus/1'>residues 241 to 250</scene> , were of interest as a potential binding site <ref name="Cordes">PMID: 15711564</ref>. Prior studies showed that deletion of these sites caused a complete inability of BbCRASP-1 to bind FH and FHL-1 regulators <ref name="Kraiczy">PMID: 14607842</ref>. The role of the C-terminus was determined by mutating <scene name='SB2013_L01gr6/Leucine_246/1'>leucine 246</scene> in this region of the dimer to aspartate <ref name="Cordes">PMID: 15711564</ref>. 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 <ref name="Cordes">PMID: 15711564</ref>. The C-terminus one monomer lies against the <scene name='SB2013_L01gr6/N-terminal_helix_ribbon/1'>N-terminal half of the E helix</scene> of the other and holds the <scene name='SB2013_L01gr6/Monomers_and_cterminus/1'>two monomers</scene> in place <ref name="Cordes">PMID: 15711564</ref>.
*CRASP-3 or ErpP


=== '''Other Potential Binding Sites''' ===
**[[4bob]] – BbCRASP-3 DISK domain<br />


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 <ref name="CordesF">PMID: 16530476</ref>. Highly conserved areas of amino acid sequences among Borrelia CRASP-1 proteins encoded by the same gene were examined. The greatest homologous region was clustered on the <scene name='SB2013_L01gr6/Pocket_region_with_blue/1'>center of the cleft region</scene> of the protein.  A binding site in this region would be probable because this area allows more contact with the regulator proteins and would aid in further evasion of the immune system by shielding the binding domain from potential detection <ref name="CordesF">PMID: 16530476</ref>.
*CRASP-4 or ErpC


== '''Discussion''' ==
**[[4bod]], [[4bxm]], [[4bf3]] – BbCRASP-4 DISK domain<br />


In order for ''B. burgdorferi'' to successfully colonize its new and hostile environment, it depends on a complement of proteins to fend off the host’s immune system. BbCRASP-1 is extremely important as it serves as a “frontier” protein, helping to bring upon successful initial infection to which depends the entire course of the pathogen’s life cycle and existence within the host. As such it remains a protein of high interest to medical researchers who can use this valuable information to stem the tide of the colonization process before it develops into a full case of Lyme disease. BbCRASP-1’s high affinity for FH and FHL-1 complement factors and other ligands such as BMP-2, Collagen I, Collagen III, Collagen
IV, fibronectin, laminin, and plasminogen make it a highly flexible and adaptive protein well suited to aiding the pathogen in colonization.


=== '''Future Studies''' ===
}}


Further work needs to be done to determine the complement regulator protein and human ligand binding sites on BbCRASP-1. Knowing this information would aid in combating Lyme disease because it would give researchers a definite target for inhibitory drugs. However, with what is known about the protein, drugs that interfere with the C-terminus region of the dimer would also aid in mediating the effects of the disease because once the dimeric state of the protein is disrupted, it cannot function. These methods should also be applied to other CRASPs so FH/FHL-1 binding would be suppressed and the host's immune system can make a sizable defense against the invading spirochete.


== References ==
== References ==


<references />
<references />
[[Category:Topic Page]]

Latest revision as of 14:36, 4 February 2025

Introduction

Lyme Disease is caused by the spirochete Borrelia burgdorferi, and is transferred into vertebrate hosts by zoonotic vectors such as Ixodes ticks [1]. Lyme disease can result in multisystemic disorders, including cardiovascular and neurological problems. 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, making it highly flexible and adaptive.

  • BbCRASP-2 interacts preferentially with factor H[4].
  • BbCRASP-3 and BbCRASP-4 belong to different strains of Borrelia burgdorferi[5].

Structure

In nature, BbCRASP-1 exists as a homodimer bound to the spirochete's surface [2]. BbCRASP-1 needs to be dimerized in order to bind FH/FHL-1 proteins. If its dimeric state is threatened, BbCRASP-1 would not be able to function.

Importance of the C-terminus

The C-terminus of BbCRASP-1 is a region crucial for its stability as a dimer. Previously,sequences of high conservation in the C-terminal regions of the protein’s monomers, , were of interest as a potential binding site [2]. Prior studies showed that deletion of these sites caused a complete inability of BbCRASP-1 to bind FH and FHL-1 regulators [3]. The role of the C-terminus was determined by mutating in this region of the dimer to aspartate [2]. 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 one monomer lies against the of the other and holds the in place [2].

Other 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 [6]. Highly conserved areas of amino acid sequences among Borrelia CRASP-1 proteins encoded by the same gene were examined. The greatest homologous region was clustered on the of the protein. A binding site in this region would be probable because this area allows more contact with the regulator proteins and would aid in further evasion of the immune system by shielding the binding domain from potential detection [6].

Function

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 Evasion

BbCRASP-1 has an affinity for Factor H (a regulatory protein secreted by the complement immune system) 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 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 [7]. As a result of this new finding, BbCRASP-1 is said to not only advocate the bypassing of the complementary immune system, but facilitate the dissemination of B. burgdorferi within the host's tissues [8]. Binding to the ECM of a host is common strategy used by pathogens to acquire contact within the host [9][10].

Discussion

In order for B. burgdorferi to successfully colonize its new and hostile environment, it depends on a complement of proteins to fend off the host’s immune system. BbCRASP-1 is extremely important as it serves as a “frontier” protein, helping to bring upon successful initial infection to which depends the entire course of the pathogen’s life cycle and existence within the host. As such it remains a protein of high interest to medical researchers who can use this valuable information to stem the tide of the colonization process before it develops into a full case of Lyme disease. BbCRASP-1’s high affinity for FH and FHL-1 complement factors and other ligands such as BMP-2, Collagen I, Collagen III, Collagen

IV, fibronectin, laminin, and plasminogen make it a highly flexible and adaptive protein well suited to aiding the pathogen in colonization.

Future Studies

Further work needs to be done to determine the complement regulator protein and human ligand binding sites on BbCRASP-1. Knowing this information would aid in combating Lyme disease because it would give researchers a definite target for inhibitory drugs. However, with what is known about the protein, drugs that interfere with the C-terminus region of the dimer would also aid in mediating the effects of the disease because once the dimeric state of the protein is disrupted, it cannot function. These methods should also be applied to other CRASPs so FH/FHL-1 binding would be suppressed and the host's immune system can mount an effective defense against the invading spirochete.

BbCRASP-1 (PDB code 1w33)

Drag the structure with the mouse to rotate

3D structure of BbCRASP3D structure of BbCRASP

Updated on 04-February-2025


ReferencesReferences

  1. ↑ 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. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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. ↑ 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
  4. ↑ Kraiczy P, Skerka C, Kirschfink M, Brade V, Zipfel PF. Immune evasion of Borrelia burgdorferi by acquisition of human complement regulators FHL-1/reconectin and Factor H. Eur J Immunol. 2001 Jun;31(6):1674-84. PMID:11385611 doi:<1674::aid-immu1674>3.0.co;2-2 10.1002/1521-4141(200106)31:6<1674::aid-immu1674>3.0.co;2-2
  5. ↑ Kraiczy P, Stevenson B. Complement regulator-acquiring surface proteins of Borrelia burgdorferi: Structure, function and regulation of gene expression. Ticks Tick Borne Dis. 2013 Feb;4(1-2):26-34. doi: 10.1016/j.ttbdis.2012.10.039., Epub 2012 Nov 10. PMID:23219363 doi:10.1016/j.ttbdis.2012.10.039
  6. ↑ 6.0 6.1 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
  7. ↑ Hallstrom T, Haupt K, Kraiczy P, Hortschansky P, Wallich R, Skerka C, Zipfel PF. Complement regulator-acquiring surface protein 1 of Borrelia burgdorferi binds to human bone morphogenic protein 2, several extracellular matrix proteins, and plasminogen. J Infect Dis. 2010 Aug 15;202(3):490-8. doi: 10.1086/653825. PMID:20565259 doi:10.1086/653825
  8. ↑ Hallstrom T, Haupt K, Kraiczy P, Hortschansky P, Wallich R, Skerka C, Zipfel PF. Complement regulator-acquiring surface protein 1 of Borrelia burgdorferi binds to human bone morphogenic protein 2, several extracellular matrix proteins, and plasminogen. J Infect Dis. 2010 Aug 15;202(3):490-8. doi: 10.1086/653825. PMID:20565259 doi:10.1086/653825
  9. ↑ Bergmann S, Lang A, Rohde M, Agarwal V, Rennemeier C, Grashoff C, Preissner KT, Hammerschmidt S. Integrin-linked kinase is required for vitronectin-mediated internalization of Streptococcus pneumoniae by host cells. J Cell Sci. 2009 Jan 15;122(Pt 2):256-67. doi: 10.1242/jcs.035600. PMID:19118218 doi:10.1242/jcs.035600
  10. ↑ Hallstrom T, Trajkovska E, Forsgren A, Riesbeck K. Haemophilus influenzae surface fibrils contribute to serum resistance by interacting with vitronectin. J Immunol. 2006 Jul 1;177(1):430-6. PMID:16785539

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