Topogenic signals

Recent results indicate that not only topogenic signals and membrane composition contribute to the proper topology of a membrane protein. The antimicrobial peptide nisin, produced by Lactococcus lactis, kills Gram-positive bacteria via pore formation, thus leading to the permeabilisation of the membrane. Nisin depends on the cell-wall precursor Lipid II, which functions as a docking molecule to support a perpendicular stable transmembrane orientation [43]. 

Swinkels, B. W., Evers, R. and Borst, P. (1988) The topogenic signal of the glycosomal (microbody) phosphoglycerate kinase of Crithidia fasciculata resides in a carboxy-terminal extension. EMBO J. 7 1159 1165. 

Wierenga, R. K., Swinkels, B. W., Michels, P. A. M. et al. (1987) Common elements on the surface glycolytic enzymes from Trypanosoma brucei may serve as topogenic signals for import into glycosomes. EM BO J 6 215-221. 

Topogenic sequences (eg, signal [amino terminal or internal] and stop-transfer) are important in determining the insertion and disposition of proteins in membranes. 

Kihara, A., and Ito, K. (1998). Translocation, folding, and stability of the hflkc complex with signal anchor topogenic sequences./. Biol. Chem. 273, 29770-29775. 

Wahlberg, J., and Spiess, M. (1997). Multiple determinants direct the orientation of signal-anchor proteins the topogenic role of the hydrophobic signal domain./ Cell... 

After synthesis of the first two transmembrane a helices, both ends of the nascent chain face the cytosol and the loop between them extends into the ER lumen. The C-terminus of the nascent chain then continues to grow into the cytosol, as it does in synthesis of type 1 and type 111 proteins. According to this mechanism, the third a helix acts as another type 11 signal-anchor sequence, and the fourth as another stop-transfer anchor sequence (see Figure 16-13d). Apparently, once the first topogenic sequence of a multipass polypeptide initiates association with the translocon, the ribosome remains attached to the translocon, and topogenic sequences that subsequently emerge from the ribosome are threaded into the translocon without the need for the SRP and the SRP receptor. 

Figure 16-15 shows the hydropathy profiles for three different membrane proteins. The prominent peaks in such plots Identify probable topogenic sequences, as well as their position and approximate length. For example, the hydropathy profile of the human growth hormone receptor reveals the presence of both a hydrophobic signal sequence at the extreme N-termlnus of the protein and an internal hydrophobic stop-transfer sequence (see Figure 16-15a). On the basis...

Topogenic sequences—N-termlnal signal sequences, Internal stop-transfer anchor sequences, and Internal signal-anchor sequences—direct the Insertion and orientation of nascent proteins within the ER membrane. This orientation is retained during transport of the completed membrane protein to its final destination. 

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