8TCB

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

8TCB の概要

• エントリーDOI: 10.2210/pdb8tcb/pdb
• 分子名称: C4b-binding protein alpha chain, M protein, POTASSIUM ION, ... (4 entities in total)
• 機能のキーワード: immune evasion, human complement, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 53430.22

構造登録者

McGowan, M.A.,Kolesinski, P.,Ghosh, P. (登録日: 2023-06-30, 公開日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.69 Å)