Protein targeting mitochondrial proteins

Venter, K. (1992). Early events in yeast mitochondrial protein targeting. Mol. Microbiol. 6,1723-1728. 

The Rieske protein in mitochondrial bci complexes is assembled when the protein is incorporated into the complex. The Rieske protein is encoded in the nucleus and synthesized in the cytosol with a mitochondrial targeting presequence, which is required to direct the apoprotein to the mitochondrial matrix. The C-terminus is then targeted back to the outside of the inner mitochondrial membrane where the Rieske cluster is assembled. In addition, the presequence is removed and the protein is processed to its mature size after the protein is inserted into the bci complex. In mammals, the presequence is cleaved in a single step by the core proteins 1 and 2, which are related to the general mitochondrial matrix processing protease (MPP) a and (3 subunits the bovine heart presequence is retained as a 8.0 kDa subunit of the complex (42, 107). In Saccharomyces cerevis-iae, processing occurs in two steps Initially, the yeast MPP removes 22 amino acid residues to convert the precursor to the intermediate form, and then the mitochondrial intermediate protease (MIP) removes 8 residues after the intermediate form is in the bci complex (47). Cleavage by MIP is independent of the assembly of the Rieske cluster Conversion of the intermediate to the mature form was observed in a yeast mutant that did not assemble any Rieske cluster (35). However, in most mutants where the assembly of the Rieske cluster is prevented, the amount of Rieske protein is drastically reduced, most likely because of instability (35, 44). 

Most of the mitochondrial proteins are nuclear encoded and thus must be targeted into mitochondria and sorted into some of their components after their synthesis at the cytosol. Because mitochondria have two membranes, there are four localization sites the matrix, the inner membrane, the intermembrane space, and the outer membrane (Fig. 6). Although there has been considerable progress in our understanding of these processes, some questions still remain. Moreover, the total picture is rather complicated and contains many exceptions. A simplified view is presented here based mainly on the view of Pfanner and Mihara (Mihara and Omura, 1996 Pfanner et al., 1997 Pfanner, 1998). There are also a number of other excellent reviews on this subject (Schatz, 1996 Stuart and Neupert, 1996 Neupert, 1997 Roise, 1997). 

Gavel, Y., and von Heijne, G. (1990). Cleavage-site motifs in mitochondrial targeting peptides. Protein Eng. 4, 33-37. 

During the process of cell death, cytochrome c is released from mitochondria into the cytosol where it assists to activate the caspases, a family of killer caspases that trigger cell death, hi this chapter evidence that transmission of cell death signals into the release of cytochrome c involves phospholipids at several stages will be presented. Thus, phospholipids target proapoptotic proteins to mitochondria, enable these or other proteins to form channels or pores and to break the mitochondrial permeability barrier. Finally, peroxidation or increased levels of disrupt the ability of cardiolipin to interact with cytochrome c, initiating a sequence of events that ultimately lead to cell death. 

Bradley PJ, Lahti CJ, Plumper E, Johnsons PJ. 1997. Targeting and translocation of proteins into the hydrogenosome of the protist Trichomonas similarities with mitochondrial protein import. EMBO J 16 3484-93. 

Anandatheerthavarada, H.K. etal. (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis./oumoi of Biological Chemistry, 274 (10), 6617-6625. 

In many ways, mitochondria resemble bacteria for example, the mitochondrial ribosomal RNA genes of all eukaryotes have been traced back to the eubacteria [10]. This can explain why some antibacterial compounds with the target of inhibiting bacterial protein synthesis also inhibit mitochondrial protein synthesis [6, 11, 12], resulting in hematotoxicity. Tetracycline, chloramphemcol and some oxazolidinone antibiotics have been shown to induce hematotoxicity by inhibiting mitochondrial protein synthesis [13]. 

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). 

Folsch H, Guiard B, Neupert W, Stuart RA (1996) Internal targeting signal of the BCS1 protein a novel mechanism of import into mitochondria. EMBO J 15 479-487 Frazier AE et al. (2004) Pam 16 has an essential role in the mitochondrial protein import motor. Nat Struct Mol Biol 11 226-233... 

Unlike Euglena PNO, which is a mitochondrial protein (Rotte et al. 2001), CpPNO lacks a mitochondrial targeting presequence and does not localize within the relic organelle (Ctrnacta et al. 2006). In fact, sporozoites of C. parvum visualized both by confocal immunofluorescence (Fig. 3) and immunogold-labelled (Fig. 4) confirm that CpPNO has an unique com-partmentalization firstly within the cytosol as expected, but secondly within... 

Of course, the stress proteins themselves may be targets for reactive metabolites or ROS, in which case the protective ability may be lost. For example, a reactive metabolite(s) of halo thane, the hepatotoxic anesthetic drug (see chap. 7), binds to hsp60 and hsp70, which are mainly mitochondrial proteins. 

All of the available evidence indicates that it is the sequence of a protein that determines its destination. Proteins targeted to pass through the inner mitochondrial or chloroplast membrane have 20- to 70-residue presequences that are rich in arginine and lysine and which are removed when the protein reaches its... 

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