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Isolated hypervariable regions derived from streptococcal M proteins specifically bind human C4b-binding protein:

E Morfeldt1, K Berggård, J Persson

  • 1Department of Medical Microbiology, Dermatology, and Infection, Lund University, Sölvegatan 23, SE-22362 Lund, Sweden.

Journal of Immunology (Baltimore, Md. : 1950)
|September 21, 2001
PubMed

Insights

Streptococcal M protein hypervariable regions (HVRs) vary greatly in sequence but bind the same complement protein, C4BP. This study shows HVRs are distinct domains retaining specific C4BP binding despite sequence and immune differences.

Area of Science:

  • Microbiology
  • Immunology
  • Structural Biology

Background:

  • Microbial surface proteins exhibit antigenic variation, posing a paradox where functional regions must also be immunologically diverse.
  • Streptococcal M proteins feature hypervariable regions (HVRs) with minimal sequence identity yet bind the same ligand, human C4b-binding protein (C4BP).

Purpose of the Study:

  • To investigate how hypervariable regions (HVRs) of streptococcal M proteins maintain specific ligand binding despite extensive sequence and immunological variation.
  • To characterize the isolated HVRs as distinct functional domains for ligand interaction.

Main Methods:

  • Synthesis of peptides representing different HVRs of streptococcal M proteins.
  • Affinity chromatography using immobilized HVR peptides to capture C4BP from human serum.
  • Inhibition experiments and structural analysis to compare binding interactions and peptide structures.

Main Results:

  • Synthetic HVR peptides retained the ability to bind C4BP, confirming HVRs as independent ligand-binding domains.
  • HVR peptides bound C4BP with high specificity, interacting with the same site on the protein.
  • Despite sequence divergence and lack of immunological cross-reactivity, HVR peptides exhibited similar structural folds.

Conclusions:

  • Streptococcal M protein HVRs can undergo extreme sequence and immunological variation while preserving specific C4BP binding.
  • The HVR functions as a distinct domain capable of maintaining specific ligand interactions independently of conserved protein regions.

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