8TGT

Structure of human C4b-binding protein alpha chain CCP domains 1 and 2 in complex with the hypervariable region of group A Streptococcus M68 protein

Summary for 8TGT

• Entry DOI: 10.2210/pdb8tgt/pdb
• Descriptor: M protein, C4b-binding protein alpha chain, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: immune evasion, human complement, immune system
• Biological source: Streptococcus pyogenes; More
• Total number of polymer chains: 3
• Total formula weight: 39947.13

Authors

Kolesinski, P.,Ghosh, P. (deposition date: 2023-07-13, release date: 2024-07-17, Last modification date: 2024-11-20)

Primary citation

Kolesinski, P.,McGowan, M.,Botteaux, A.,Smeesters, P.R.,Ghosh, P.
Conservation of C4BP-binding sequence patterns in Streptococcus pyogenes M and Enn proteins.
J.Biol.Chem., 300:107478-107478, 2024

PubMed Abstract: 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.

PubMed: 38879009
DOI: 10.1016/j.jbc.2024.107478

Experimental method

X-RAY DIFFRACTION (2.5 Å)