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<StructureSection load='1w33' size='350' side='right' scene='SB2013_L01gr6/Bbcrasp-1_no_spacefill/2' caption='BbCRASP-1 (PDB code [[1w33]])'>
== '''Introduction'''  ==
== '''Introduction'''  ==


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.  
[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.


<applet load='BBCRASP-12' size='400' frame='true' align='right' caption='BbCRASP-1' scene='Insert optional scene name here' />
*'''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>.


<scene name='SB2013_L01gr6/Bbcrasp1/2'>BbCRASP1</scene>
=== '''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 <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''' ==


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.   
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 <ref name="Bykowski">PMID: 17562769</ref>. BbCRASP-1 provides resistance for the spirochete against the host's complementary immune system as well as spreading of the spirochete within the host.   


=== '''Bypassing the Host's Immune Response''' ===
=== '''Host 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 effectivly able to infiltrate the host and go undetected in the host's plasma(Bykowski 2007).
BbCRASP-1 has an affinity for [http://www.uniprot.org/uniprot/CFAH_HUMAN Factor H] (a regulatory protein secreted by the [http://en.wikipedia.org/wiki/Complement_system 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<ref name="Bykowski">PMID: 17562769</ref>.
==== '''Factor H''' ====
Factor H is a complement control protein that can be found in plasma. It functions as a regulator
that directs the complement system to pathogens so they don't harm the host (Alitalo
2002).


=== '''Relation to the Extra Cellular Matrix''' ===
=== '''Relation 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(bone morphogenetic protein 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).
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''' ==
 
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.
</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 />
 
*CRASP-2 or CspZ
 
**[[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 />
 
*CRASP-3 or ErpP


== '''Structure''' ==
**[[4bob]] – BbCRASP-3 DISK domain<br />
 
*CRASP-4 or ErpC
 
**[[4bod]], [[4bxm]], [[4bf3]] – BbCRASP-4 DISK domain<br />
 
 
}}
 
 
== References ==


The two monomers (blue & green) are connected together at the C-terminus
<references />
(purple) to form the dimer. The C-terminus is of significance because it was thought
[[Category:Topic Page]]
to be the binding site of the BbCRASP-1 protein because when the C-terminus
(residues 241-250) was truncated, BbCRASP-1 was no longer able to bind to factor H
(Cordes 2005). Through experimentation, it was suggested that the C-terminus is
actually not the binding sight but a region that controls the structure of the protein.
truncation of the C-terminus (241-250) causes the structure of the protein to change
which causes factor H to not bind. To further test this, a buried leucine(residue 246)
in the C-terminus (yellow) was mutated and replaced by aspartate. this also caused
the protein to not bind to factor H. It was then concluded that the C-terminus is a
structurally sensitive region rather than a direct binding site (cordes 2005).

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