The expanding role of the ER translocon in membrane protein folding

Abstract

Eukaryotic polytopic membrane proteins are cotranslationally inserted into the ER membrane by a multisubunit protein-conducting channel called the Sec61 translocon. Although most major translocon components have been identified and reconstituted, their stoichiometry and functional organization remain unknown. This has led to speculative and sometimes conflicting models describing how multiple transmembrane (TM) segments might be oriented and integrated during nascent polytopic protein biogenesis. Kida et al. (see p. 1441 of this issue) shed new insight into this area by demonstrating that functional translocons exhibit a remarkable flexibility by simultaneously accommodating at least two hydrophilic translocating peptides that are separated by multiple hydrophobic TMs. These surprising findings support an expanded role for the translocon in membrane protein biogenesis and require reassessment of current views based on a single small functional pore.

Figure 1.

Potential orientation of multiple peptide segments in the translocon. (A) Truncated integration intermediates of Kida et al. (2007) showing N- and C-terminal hydrophilic peptides (dashed lines) and hydrophobic TMs (yellow ovals) retained in a TM orientation within the translocon (blue disc) by cytosolic streptavidin (SA)-avidin binding peptide (ABP) and peptidyl tRNA. In both intermediates, release of SA with biotin results in N terminus translocation. (B) Potential configurations of Sec61αβγ heterotrimer (gray cylinder) within an assembled translocon. Four subunits with lateral exit sites (arrows) accommodate only one TM, whereas (ii) two front-to-front subunits, (iii) four front-to-front subunits, or (iv) a single large pore could potentially accommodate multiple peptide regions.