Outer mitochondrial membrane protein insertion

The nuclear-encoded proteins are inserted into both inner and outer mitochondrial membranes, the intermembrane space, and the matrix and there are several different mechanisms involved. As mentioned above there is no apparent requirement for a presequence on proteins which insert specifically into the mitochondrial outer membrane. For proteins destined for the inner mitochondrial membrane, a stop-transfer mechanism is proposed. Thus some information in the peptide must stop the complete transfer of the protein into the mitochondrial matrix, enabling the protein to remain in the inner mitochondrial membrane. For some proteins in the intermembrane space (for example the Rieske iron-sulphur protein associated with the outer face of complex III), a particularly complicated import pathway... 

Figure 3. Possible mechanisms of actions of Bcl-2 members. Two prevailing models through which Bcl-2 membas trigger cytochrome c release have been suggested. In both models phospholipids in the bilayer stnicture either individually and/or collectively induce a conformational change in Bcl-2 members, allowing them to insert into the outer mitochondrial membrane. In model 1 proapoptotic proteins destabilize the outer mitochondrial membrane, oligomerize and form channels through which cytochrome c and other proteins of the intermembrane space can escape.BcI-2 proteins such as Bax or tBid act in concert with other proteins of the BcI-2 family to form channels. In model 2 Bcl-2 members such as Bax interact with residoit proteins in the outer membrane (OM) such as the voltage-dependent anion...

The Bcl-2 family of proteins are considered as apoptosis regulating proteins. Members of this family are the Bcl-2 and Bcl-xL which are anti-apoptotic while Bax, Bad, Bid, Bim are pro-apoptotic. Fro-apoptotic and anti-apoptotic Bcl-2 proteins can bind directly to the components of mitochondrial pore, leading to either its opening or closure respectively.16 Figure 1. Alternatively, pro-apoptotic members, such as Bak or Bax, insert into the outer mitochondrial membrane where they oligomerize to form a permeable pore.17 Furthermore, an interaction between the intrinsic and the extrinsic... 

The space between the inner and outer mitochondrial membrane can be reached by proteins that have two signal peptides. The first inserts the protein into the membrane and is cleaved in the matrix the second remains and directs the protein to the intermembrane space. 

The antiapoptotic Bcl-2 -type proteins (including Bcl-2, Bcl-xL, Bcl-wL) have at least two ways of antagonizing death signals. They insert into the outer mitochondrial membrane to antagonize channel-forming pro-apoptotic factors, therby decreasing cytochrome c release. They may also bind cytoplasmic Apaf so that it cannot form the apoptosome complex (Fig. 18.16). 

Inner and outer mitochondrial membranes are specialized modifications of a large family of membranes that includes the nuclear and the plasma membranes and the membranes of the endoplasmic reticulum. Mitochondrial membranes function as selective barriers that are also capable of active transport and provide a framework on which catalytic proteins (e.g., those of the respiratory chain) are tightly inserted in a pattern compatible with maximum efficiency. Like other membranes, mitochondrial membranes are composed of lipids and protein molecules—the fundamental building blocks. However, some features are unique to the mitochondria. For example, the mitochondrial membranes contain a lipid cardiolipin not found in the plasma membrane. 

The above describes the major pathway of proteins destined for the mitochondrial matrix. However, certain proteins insert into the outer mitochoiidrial membrane facilitated by the TOM complex. Others stop in the intermembrane space, and some insert into the inner membrane. Yet others proceed into the matrix and then return to the inner membrane or intermembrane space. A number of proteins contain two signaling sequences—one to enter the mitochondrial matrix and the other to mediate subsequent relocation (eg, into the inner membrane). Certain mitochondrial proteins do not contain presequences (eg, cytochrome Cy which locates in the inter membrane space), and others contain internal presequences. Overall, proteins employ a variety of mechanisms and routes to attain their final destinations in mitochondria. 

Most of the responses which lead to cytochrome c release are triggered by activated proapoptotic members of the Bcl-2 family which are directed to mitochondria, where they insert into the outer membrane. What mediates the specific targeting of these proteins to mitochondria, hi a recent work, Lutter et al. (2000) investigated this question using the proapoptotic Bcl-2 member (tBid) as a tool. These authors estabhshed a hposome model for cytochrome c release and recreated the lipid constitution of mitochondrial outer... 

The first condition is met by having a series of four protein complexes, inserted into the mitochondrial inner membrane, each made up of a number of electron (and sometimes proton) acceptors of increasing redox potential. Three of them (Complexes I, III, and IV) are presented in cartoon form in Figure 5.18. Complex I, referred to more prosaically as NADH-Coenzyme Q oxidoreductase, transfers electrons stepwise from NADH, through a flavo-protein (containing FMN as cofactor) to a series of iron—sulfur clusters (of which more in Chapter 13) and ultimately to coenzyme Q, a lipid-soluble quinone, which transfers its electrons to Complex III. The AE o for the couple NADH/CoQ is 0.36 V, corresponding to a AG° of —69.5 kJ/mol, and in the process of electron transfer, protons are exported into the intermembrane space (between the mitochondrial inner and outer membranes). 

Liver CPTi Can Insert Into the Endoplasmic Reticulum in a Cell Free-System. The cDNA for rat hver CPTi (an integral protein in the mitochondrial outer membrane) predicts a polypeptide of 773 amino acids (88kDa). Unlike CPT2 (the latent mitochondrial CPT), no N-tenninal signal peptide is cleaved from nascent CPTi during... 

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