A mechanism for toxin insertion into membranes is suggested by the crystal structure of the channel-forming domain of colicin E1

Abstract

On the basis of the structure of the colicin E1 channel-forming domain, its comparison with the structure of the colicin A domain and the known requirement for initial electrostatic and subsequent hydrophobic interactions, molecular details of the docking, unfolding and insertion of the channel-forming domain into the membrane are proposed. The model for docking and initial interaction with the membrane positions the hydrophobic hairpin 'anchor' approximately parallel to the membrane surface. Hydrophobic interactions in the docking layer may then be displaced by interactions with the membrane, spreading the helices on the surface and exposing the hydrophobic hairpin for insertion into the membrane.

Bcl-2 family proteins as ion-channels

“…The Bcl-X L structure bears a striking resemblance to the previously solved structures of the diphtheria toxin membrane-translocation domain (Choe et al, 1992) and the poreforming domains of colicins A and E1 (Parker et al, 1992;Elkins et al, 1997). The diphtheria toxin, produced by Corynebacterium diphtheriae, is composed of two parts: the A and B fragments, which possess ADP-ribosylation and pore-forming activity, respectively (London, 1992).…”

“…The colicin E1 channel is predicted to consist of a bundle of four a-helices, two hydrophobic, and two amphipathic, which penetrate the membrane bilayer spontaneously and upon imposition of a trans-negative membrane potential, respectively (Elkins et al, 1997). Although Bcl-2 would be predicted to possess only two helices of sufficient length to span a membrane bilayer, two Bcl-2 monomers could come together to form a four helix bundle, with each contributing two a-helices to the channel.…”

Structural studies of apoptosis and ion transport regulatory proteins in membranes

“…51,52 Membrane association occurs when the colicin soluble helical bundle unfolds, exposing the hydrophobic helical hairpin which inserts in the membrane, while the rest of the protein forms a helical network on the membrane surface, adopting a so-called umbrella conformation. 50,53 The solid-state NMR data in Fig. 3(A) suggest that Bcl-xL associates with membranes in a similar fashion, as illustrated in Fig.…”

TCTP protects from apoptotic cell death by antagonizing bax function

“…The structure of Bcl-xL 25 revealed a similarity between its H5-H6 and the channel-forming domains of diphtheria toxin and bacterial colicins A and E1. 23 With the determination of a number of structures of proteins from the Bcl2 family, 17 it has become clear that pro-and antiapoptotic members of the family have similar folds with the central core helices H5-H6 flanked by the other a-helices and function as regulators of the mitochondrial membrane permeability where they would influence the opening of specialized pores. 17,[24][25][26][27] It is presumed today that the balance between the pro-apoptotic and the antiapoptotic will define the level of permeability of those pores rather than the helices creating the pores.…”

“…In particular, the pair of helices H2-H3 bear structural resemblance to the transmembrane domains of diphtheria toxin and bacterial colicins 23 and to the pair of helices H5-H6 in Bcl2 family proteins 17,[24][25][26][27] such as Bax, 18 despite negligible amino acid homology. It should be noted that there is no striking amino acid homology between the members of the Bcl2 family in the domain encompassing these H5-H6 (or H6-H7) pore-forming helices but, only a structural similarity.…”