SUMMARY PARAGRAPH for SEC61
Sec61p, an essential yeast protein, is the largest and major subunit of the heterotrimeric Sec61 complex, also referred to as the translocon (4; reviewed in 1). The Sec61 complex forms a channel in the endoplasmic reticulum (ER) membrane and mediates translocation of secretory and membrane proteins into the ER and also retrograde transport of misfolded proteins to the cytoplasm for degradation (reviewed in 5 and 1). The other subunits of the Sec61 complex are Sss1p, an essential protein thought to stabilize the complex, and Sbh1p (6, 7, 8).
Proteins that are transported into or across the ER membrane are directed there by signal sequences or by transmembrane segments that interact with the translocation apparatus. In S. cerevisiae the Sec61 complex mediates both co- and posttranslational translocation (while the mammalian Sec61 complex functions primarily with the cotranslational pathway; 9). During cotranslational translocation, ribosomes synthesizing signal sequence-containing proteins are targeted to the translocon via the signal recognition particle (SRP), and the ribosomes bind directly to Sec61p such that protein biosynthesis and translocation are synchronous (10). Posttranslational translocation requires Sec62p, Sec63p, Sec66p, and Sec72p (comprising the Sec63 complex), as well as Kar2p, in place of SRP to facilitate interaction of the full-length polypeptide with the translocon via the signal sequence (11, 12). S. cerevisiae contains a second Sec61-like complex involved in cotranslational translocation called the Ssh1p complex (containing Ssh1p, Sbh2p, and Sss1p; 13 and reviewed in 14).
Retrograde transport of misfolded proteins into the cytoplasm (also called dislocation) employs the Sec61 channel via interaction with the 19S proteasome regulatory particle (15). This interaction, which competes with the ribosome-Sec61p interaction, defines the Sec61 complex as the principal proteasome receptor in the ER membrane (15).
Sec61p contains 10 membrane spans separated by loops; the amino and carboxy termini and loops L2, L4, L6, and L8 face the cytoplasm (16). Structural studies of the conserved complex from Methanococcus jannaschii indicate that Sec61p forms two linked halves, transmembrane segments 1-5 and 6-10, that are clamped together by Sss1p; a side view of this structure reveals an hourglass shape with a hydrophilic conduit through the center (17). Transmembrane domain 2 (TM2) creates a channel 'plug' that is required to maintain a closed state (18). Interaction of Sec61p with Sss1p involves the region that includes TM6, TM7, and TM8 (7). Mutant analyses indicate that L6 and L8 are required for translocation of proteins that use the cotranslational pathway, with residues in L8 mediating normal affinity for 80S ribosomes but not required for proteasome binding (19, 20). TM3 and the fourth luminal loop are required for normal dislocation of a misfolded protein (21, 22).
Sec61p is widely conserved; the mammalian ortholog, Sec61alpha, and the archael ortholog SecY have been extensively studied and the mechanism of translocation is thought to be conserved among all species (reviewed in 23 and 24).
Last updated: 2007-10-03