Protein targeting signal peptidase

Cleavage occur s at the scissile bond. Residues in the substrate towards the N-terminus are numbered PI, P2, P3, etc, whereas residues towards the C-terminus are numbered PI, P2, P3 etc. Cleavage occurs between PI and P1. For a peptidase with limited specificity, only the residue in PI or PI is important for specificity. A peptidase with an extended substrate binding site will have a preference for residues in other positions. For example cathepsin L prefers substrates with phenylalanine in P2 and arginine in PI. However, this is a preference only, and cathepsin L cleaves substrates after other amino acids. Caspase-3 has a preference for Asp in both P4 and PI, but it is unusual for substrate specificity to extend much further from the scissile bond. The peptidase with the most extended substrate specificity may be mitochondrial intermediate peptidase that removes an octopeptide targeting signal from the N-terminus of cytoplasmically synthesized proteins that are destined for import into the mitochondrial lumen. 

This a-helix is amphipathic, containing patches of positively charged and hydrophobic amino acids, respectively, on opposite surfaces of the theoretical cylinder. The presequence is usually processed by the mitochondrial processing peptidase (MPP) and the mature protein is sorted to either the matrix, or to the inner membrane if it bears a hydrophobic stop-transfer sequence. Some mitochondrial proteins, mostly destined to the membranes, do not have cleavable N-terminal presequences but have internal targeting signals that are not well characterized (Pfanner and Geissler 2001). 

Penicillins have been considered for the inhibition of other bacterial serine enzymes than the DD-peptidases and /3-lactamases. For instance, bacterial signal peptidases (SPases) are essential for cell viability and therefore represent nowadays a class of novel antibacterial target <1998NAT186>. SPases are involved in protein translocation through the cytoplasmic membrane in the final step of the bacterial protein secretion pathway <1997PSC1119>. 5(S)-Stereoisomers of penems have been found to inhibit SPases <1995BML443>. The most potent inhibitors are 5/AV-tricyclic penems <2003S1732>. 

Figure 30.31 The SRP targeting cycle, (1) Protein synthesis begins on free ribosomes. (2) After the signal sequence has exited the ribosome, it is bound by the SRP, and protein synthesis halts. (3) The SRP-ribosome complex docks with the SRP receptor in the ER membrane. (4) The SRP and SRP receptor simultaneously hydrolyie bound GlPs. Protein synthesis resumes and the SRP is free to bind another signal sequence, (5) The signal peptidase may remove the signal sequence as it enters the lumen of the ER, (6) Protein synthesis continues as the protein is synthesized directly into the ER. (7) On completion of protein synthesis, the ribosome is released and the protein tunnel in the translocon closes. [After H. Lodish et al. Molecular Cell Biology, 5th ed, (W. H. Freeman and Company. 2004), Fig. 16.6,]...

---