Presenilin adopts the ClC channel fold

Abstract

Presenilin is an integral membrane aspartate protease that regulates cellular processes by cleaving proteins within the cell membrane. The recent crystal structure of presenilin reveals a conspicuous pore in a bundle of nine α-helices, which was originally thought to adopt a novel protein fold. However, here I show that the presenilin fold is a variant of the ClC chloride channel/transporter fold. This observation may have important implications for presenilin's postulated biological role as a calcium leak channel.

Keywords: ClC channel; calcium leak channel; presenilin; protein fold.

Figure 1

Secondary structure cartoons of PSH and ClC proteins. The protein chains are colored blue to red proceeding from the N‐terminus to the C‐terminus. The view is perpendicular to the plane of the membrane, looking “down” the helices, with the N‐terminus of the first helix (helix A, blue) facing the viewer. Note that in both proteins the polarity of the corresponding α‐helices is identical, e.g., the N‐terminus of the yellow helix E is pointing toward the viewer. (a) PSH tetramer (PDB ID: 4HYG ). Only chain A (one of the monomers) is shown in rainbow colors; the remaining three subunits are white and light blue. (b) Escherichia coli ClC chloride channel (PDB ID: 1OTS). The first internal tandem domain is shown in rainbow colors, while the second internal tandem domain, oriented antiparallel to the first, is colored grey. A pink star indicates the general location of bound chloride. In this representation, ClC helix B is considered a single transmembrane helix interrupted by a short transverse loop; in Ref. 6 this helix is represented as two stacked helices, neither of which fully crosses the membrane.

Figure 2

Schematic representation of the seven‐helix ClC and GPCR folds. Helices are shown as circles, in an idealized view analogous to Figure 1, looking “down” the helices and perpendicular to the plane of the membrane. The protein chains are colored blue to red proceeding from the N‐terminus to the C‐terminus, with the seven successive α‐helices lettered from A to G. Solid lines represent interhelical loops on the viewer side of the membrane; dashed lines represent interhelical loops on the opposite, far side of the membrane. (a) The ClC/PSH fold. (b) The GPCR/bacteriorhodopsin fold.