Diphtheria Toxin - Structure

Structure

Diphtheria toxin is a single polypeptide chain of 535 amino acids consisting of two subunits linked by disulfide bridges, known as an A-B toxin. Binding to the cell surface of the B subunit (the less stable of the two subunits) allows the A subunit (the more stable part of the protein) to penetrate the host cell.

The crystal structure of the diphtheria toxin homodimer has been determined to 2.5A resolution. The structure reveals a Y-shaped molecule consisting of 3 domains. Fragment A contains the catalytic C domain, and fragment B consists of the T and R domains

  • The N-terminal catalytic domain, known as the C domain, has an unusual beta+alpha fold. The C domain blocks protein synthesis by transfer of ADP-ribose from NAD to a diphthamide residue of EF-2.
  • A central translocation domain, known as the T domain or TM domain. The T domain has a multi-helical globin-like fold with two additional helices at N-termini, but which has no counterpart to the first globin helix. This domain is thought to unfold in the membrane. pH-induced conformational change in the T domain triggers insertion into the endosomal membrane and facilitates the transfer of the C domain into the cytoplasm.
  • A C-terminal receptor-binding domain, known as the R domain. This domain has a beta-sandwich fold consisting of nine strands in two sheets with greek-key topology; it is a subclass of immunoglobin-like fold. The R domain binds to cell surface receptor, permitting the toxin to enter the cell by receptor mediated endocytosis.

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