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==Structure of human C4b-binding protein alpha chain CCP domains 1 and 2 in complex with the hypervariable region of group A Streptococcus M87 protein==
<StructureSection load='8tcb' size='340' side='right'caption='[[8tcb]], [[Resolution|resolution]] 2.69&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8tcb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Streptococcus_pyogenes Streptococcus pyogenes]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8TCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8TCB FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.69&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8tcb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8tcb OCA], [https://pdbe.org/8tcb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8tcb RCSB], [https://www.ebi.ac.uk/pdbsum/8tcb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8tcb ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/C4BPA_HUMAN C4BPA_HUMAN] Controls the classical pathway of complement activation. It binds as a cofactor to C3b/C4b inactivator (C3bINA), which then hydrolyzes the complement fragment C4b. It also accelerates the degradation of the C4bC2a complex (C3 convertase) by dissociating the complement fragment C2a. Alpha chain binds C4b. It interacts also with anticoagulant protein S and with serum amyloid P component.
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== Publication Abstract from PubMed ==
Antigenically sequence variable M proteins of the major bacterial pathogen Streptococcus pyogenes (Strep A) are responsible for recruiting human C4b-binding protein (C4BP) to the bacterial surface, which enables Strep A to evade destruction by the immune system. The most sequence divergent portion of M proteins, the hypervariable region (HVR), is responsible for binding C4BP. Structural evidence points to the conservation of two C4BP-binding sequence patterns (M2 and M22) in the HVR of numerous M proteins, with this conservation applicable to vaccine immunogen design. These two patterns, however, only partially explain C4BP binding by Strep A. Here, we identified several M proteins that lack these patterns but still bind C4BP and determined the structures of two, M68 and M87 HVRs, in complex with a C4BP fragment. Mutagenesis of these M proteins led to the identification of amino acids that are crucial for C4BP binding, enabling formulation of new C4BP-binding patterns. Mutagenesis was also carried out on M2 and M22 proteins to refine or generate experimentally grounded C4BP-binding patterns. The M22 pattern was the most prevalent among M proteins, followed by the M87 and M2 patterns, while the M68 pattern was rare. These patterns, except for M68, were also evident in numerous M-like Enn proteins. Binding of C4BP via these patterns to Enn proteins was verified. We conclude that C4BP-binding patterns occur frequently in Strep A strains of differing M types, being present in their M or Enn proteins, or frequently both, providing further impetus for their use as vaccine immunogens.

Conservation of C4BP-binding sequence patterns in Streptococcus pyogenes M and Enn proteins.,Kolesinski P, McGowan M, Botteaux A, Smeesters PR, Ghosh P J Biol Chem. 2024 Jul;300(7):107478. doi: 10.1016/j.jbc.2024.107478. Epub 2024 , Jun 13. PMID:38879009<ref>PMID:38879009</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8tcb" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Streptococcus pyogenes]]
[[Category: Ghosh P]]
[[Category: Kolesinski P]]
[[Category: McGowan MA]]