a signal-recognition particle (srp) Directs the er signal sequence to a specific receptor in the rough er membrane
The ER signal sequence is guided to the ER membrane by at least two components: a signal-recognition particle (SRP), which cycles between the ER membrane and the cytosol and binds to the signal sequence, and an SRP receptor in the ER membrane. The SRP is a large complex; in animal cells, it consists of six different polypeptide chains bound to a single small RNA molecule. While the SRP and SRP receptor have fewer subunits in bacteria, homologs are present in all cells, indicating that this protein-targeting mechanism arose early in evolution and has been conserved.
ER signal sequences vary greatly in amino acid sequence, but each has eight or more nonpolar amino acids at its center (see Table 12–3, p. 648). How can the SRP bind specifically to so many different sequences? The answer has come from the crystal structure of the SRP protein, which shows that the signal-sequence-binding site is a large hydrophobic pocket lined by methionines. Because methionines have unbranched, flexible side chains, the pocket is sufficiently plastic to accommodate hydrophobic signal sequences of different sequences, sizes, and shapes.
The SRP is a rodlike structure, which wraps around the large ribosomal subunit, with one end binding to the ER signal sequence as it emerges from the ribosome as part of the newly made polypeptide chain; the other end blocks the elongation factor binding site at the interface between the large and small ribosomal subunits (Figure 12–36). This block halts protein synthesis as soon as the signal peptide has emerged from the ribosome. The transient pause presumably gives the ribosome enough time to bind to the ER membrane before completion of the polypeptide chain, thereby ensuring that the protein is not released into the cytosol. This safety
Figure 12–36 The signal-recognition particle (SRP). (a) a mammalian srp is a rodlike ribonucleoprotein complex containing six protein subunits (brown) and one rna molecule (blue). The srp rna forms a backbone that links the protein domain containing the signal-sequencebinding pocket to the domain responsible for pausing translation. Crystal structures of various srp pieces from different species are assembled here into a composite model to approximate the structure of a complete srp. (B) The three-dimensional outline of the srp bound to a ribosome was determined by cryoelectron microscopy. srp binds to the large ribosomal subunit so that its signal-sequence-binding pocket is positioned near the growing polypeptide chain exit site, and its translational pause domain is positioned at the interface between the ribosomal subunits, where it interferes with elongation factor binding. (C) as a signal sequence emerges from the ribosome and binds to the srp, a conformational change in the srp exposes a binding site for the srp receptor. (B, adapted from m. halic et al., Nature 427:808–814, 2004. With permission from macmillan publishers ltd.) device may be especially important for secreted and lysosomal hydrolases, which could wreak havoc in the cytosol; cells that secrete large amounts of hydrolases, however, take the added precaution of having high concentrations of hydrolase inhibitors in their cytosol. The pause also ensures that large portions of a protein that could fold into a compact structure are not made before reaching the translocator in the ER membrane. Thus, in contrast to the post-translational import of proteins into mitochondria and chloroplasts, chaperone proteins are not required to keep the protein unfolded.