Protein translocation through membrane

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>. 

Vivi-s, E., Brodin, P., and Lebleu, B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J. Biol. Chem. 1997, 272, 16010-16017. 

However, not all proteins proceed directly to their eventual destination. Some proteins relocate from one plasma membrane compartment to another by means of trans-cytosis. Transcytosis involves endocytosis of selected proteins in one membrane compartment, followed by subsequent transport through early endosomes to recycling endosomes and finally translocation to a different membrane compartment, for example from the apical to the basolateral surfaces. Sorting at the TGN and endo-some recycling steps appear to have a primary role in the steady state distribution of proteins in different plasma membrane domains [47], However, selective retention of proteins at the plasma membrane by scaffolding proteins or selective removal may also contribute to normal distributions. Finally, microtubule-motor regulatory mechanisms have been discovered that might explain the specific delivery of membrane proteins to discrete plasma membrane domains [48]. 

As mentioned above, transport of siderophores across the cytoplasmic membrane is less specific than the translocation through the outer membrane. In E. coli three different outer membrane proteins (among them FepA the receptor for enterobactin produced by most E. coli strains) recognise siderophores of the catechol type (enterobactin and structurally related compounds), while only one ABC system is needed for the passage into the cytosol. Likewise, OM receptors FhuA, FhuE, and Iut are needed to transport a number of different ferric hydroxamates, whereas the FhuBCD proteins accept a variety of hydroxamate type ligands such as albomycin, ferrichrome, coprogen, aerobactin, shizokinen, rhodotorulic acid, and ferrioxamine B [165,171], For the vast majority of systems, the substrate specificity has not been elucidated, but it can be assumed that many siderophore ABC permeases might be able to transport several different but structurally related substrates. 

As described in Section II,A, gram-positive bacteria have only one membrane (the cytoplasmic membrane). Therefore, the translocation through the Sec pathway directly leads proteins to be secreted (Simonen and Palva, 1993 Nagarajan, 1993). The issue of protein sorting into the cell wall is described in a separate section. 

Hagting A, Karlsson C, Clute P, Jackman M, Pines J (1998) MPF localization is controlled by nudear export. EMBO J 17 4127-4138 Hamman BD, Chen JC, Johnson EE, Johnson AE (1997) The aqueous pore through the translocon has a diameter of 40-60 A during cotranslational protein translocation at the ER membrane. Cell 89 535-544 Hampton RY, Rine J (1994) Regulated degradation of HMG-CoA reductase, an integral membrane protein of the endoplasmic reticulum, in yeast. J Cell Biol 125 299-312... 

Secretory proteins have an N-terminal signal peptide which targets the protein to be synthesized on the rough endoplasmic reticulum (RER). During synthesis it is translocated through the RER membrane into the lumen. Vesicles then bud off from the RER and carry the protein to the Golgi complex, where it becomes glycosylated. Other vesicles then carry it to the plasma membrane. Fusion of these transport vesicles with the plasma membrane then releases the protein to the cell exterior. 

Three different assembly pathways have been suggested for the imported inner membrane proteins. All three utilize the so-called TOM complex for translocation through the outer membrane. Two of the pathways further make use of the same TIM23 complex in the inner membrane that also handles soluble matrix proteins the third involves both a distinct set of chaperones in the intermembrane space as well as a distinct inner membrane insertion machinery, the TIM22 complex. 

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