1/3/2024 0 Comments Alpha helix er lumen![]() It is thus clear that additional factors contribute to topogenesis. The effect of the flanking charges on the orientation of the signal is most likely due to electrostatic interactions with charges at or near the translocon.Īlthough several studies have shown that mutations of charged residues flanking a signal sequence affect its orientation, an asymmetric distribution of charges is often not sufficient to generate a uniform topology of the mutant proteins (e.g. The more positively charged flanking sequence is usually found on the cytosolic side of the membrane in both prokaryotic and eukaryotic cells (the positive-inside and charge difference rules von Heijne, 1986 Hartmann et al., 1989). The most prominent determinant of signal orientation is the distribution of charged amino acids on either end of the hydrophobic sequence. Reverse signal–anchor sequences, in contrast, acquire the opposite N exo/C cyt orientation, as is the case, for example, in the cytochromes P450. In both cases, the polypeptide transiently forms a loop while protein synthesis is still ongoing. many glycosyltransferases), anchoring the polypeptide in an N cyt/C exo orientation in the bilayer. The same orientation is attained by uncleaved signal–anchor sequences of type II membrane proteins (e.g. Cleavable signals of secretory and type I membrane proteins ultimately expose the C-terminal cleavage site to signal peptidase on the lumenal surface of the ER membrane, the N-terminus thus pointing towards the cytosol. In addition to their function in targeting, signal sequences play an important role in protein topogenesis by orienting themselves in the translocon and the membrane ( Spiess, 1995). Site-specific photocrosslinking has shown that the hydrophobic segment of the signal contacts a defined site in Sec61α as well as lipids, indicating that the signal sequence is specifically situated at the interface between the channel and the surrounding lipids ( High et al., 1993 Jungnickel and Rapoport, 1995 Martoglio et al., 1995 Mothes et al., 1998). ![]() SRP is then released, and the signal is transferred to the translocon by an unknown mechanism. Upon GTP hydrolysis, the ribosome engages with the translocon, which is composed of 3–4 Sec61 complexes ( Hartmann et al., 1994 Hanein et al., 1996 Wang and Dobberstein, 1999), and resumes translation. This process is regulated by three GTPases: the 54 kDa subunit of SRP (SRP54) and the two subunits of SR ( Connolly and Gilmore, 1993 Miller et al., 1993 Powers and Walter, 1995 Rapiejko and Gilmore, 1997 Song et al., 2000). The signal is first recognized by the signal recognition particle (SRP), which associates with the ribosome–nascent chain complex, slows down translation, and targets the complex to the ER membrane by binding to the SRP receptor (SR) ( Keenan et al., 2001). Sorting of proteins to the mammalian endoplasmic reticulum (ER), for secretion or for insertion into the membrane, is mediated by a signal sequence that is characterized by a stretch of 7–25 mainly apolar residues ( Walter and Johnson, 1994). ![]()
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