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Complement Regulator-Acquiring Surface Protein: Difference between revisions

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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_246/2'>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>.
*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_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>.
*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]]

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