Peptide translocation

Brandi, L., Fabbretti, A., Di Stefano, M., Lazzarini, A., Abbondi, M., and Gualerzi, C. O. (2006a). Characterization of GE82832, a peptide translocation inhibitor interacting with bacterial 30S ribosomal subunits, /v Al l 12, 1262—1270. 

Matsuzaki K, Murase O, Fujii N, Miyajima K (1996) An antimicrobial peptide, magainin 2, induced rapid flip-flop of phospholipids coupled with pore formation and peptide translocation. Biochemistry-Us 35 11361-11368... 

The path that leads from full sized protein to epitopes at the cell surface is complex, consisting of the generation of small peptides, translocation of the peptides to the endoplasmic reticulum by a transporter complex, loading of the peptides onto MHC class-I molecules and relocation of the MHC class-I-peptide complex to the cell surface (Rock and Goldberg, 1999). Since many of these steps are known to be prime targets for viral evasion strategies, the next step was to identify at what point the GAr interferes with the presentation of EBNAl. 

To model the proteasome mechanism, one should adequately describe three essential processes involved in the proteasome function selection of cleavage sites, kinetics of generated fragments, and a peptide translocation inside the proteasome (see Fig. 14.2). At the moment there is no model which describe adequately all these factors. In this paper we describe these modeling approaches and discuss how one can merge them. It is important to note also that for different situations different models should be used, depending on which factor provides the largest influence on the phenomenon studied. 

Proteins are targeted to various locations after synthesis by signal sequences. Thus, proteins destined for the ER, the mitochondria and chloroplasts have particular kinds of signal sequences at the N-terminus. ER-targeted proteins enter the ER directly off rough ER ribosomes via a signal recognition particle (SRP) complex that is linked to an SRP receptor and a ribosome receptor-transmembrane peptide translocation complex associated with the ER membrane. Within, the ER polypeptides are processed and folded and S—S links are formed. 

Lapinski, P.E.. Neubig, R.R.. and Raghavan, M. (2001) Walker A lysine mutations of TAPI and TAP2 interfere with peptide translocation but not peptide binding. The Journal of Biological Chemistry, 276 (10), 7526-7533. 

Chakrabarti, A. C. and Deamer, D. W. (1994). Permeation of membranes by the neutral form of amino acids and peptides relevance to the origin of peptide translocation. Journal of Molecular Evoution, 39, 1-5. 

A further functionally diverse class is made up of the proteins involved in protein biosynthesis and membrane transport. GTPases with functions in protein biosynthesis include the elongation factors, termination factors and peptide translocation factors. These are mostly monomeric proteins with molecular weights of 40 - 50 kDa. 

Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ. Ploegh HL, Peterson PA, Yang Y, Fruh K (1997) The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6 613-621... 

Compels UA, Macaulay HA (1995) Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication. J Gen Virol 76 451-458 Goodbourn S, Didock L, Randall RE (2000) Interferons cell signalling, immune modulation, antiviral responses and viral countermeasures. J Gen Virol 81 2341-2364 Hengel H, Flohr T, Hammerling GJ, Koszinowski UH, Momburg F (1996) Human cytomegalovirus inhibits peptide translocation into the endoplasmic reticulum for MHC class I assembly. J Gen Virol 77 2287-2296... 

Lehner PJ, Karttunen JT, Wilkinson GW, Cresswell P (1997) The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci USA 94 6904 6909... 

Akin to the findings with ICP47, gpUS6-mediated inhibition of TAP is species specific. Peptide translocation assays using cells infected with a gpUS6-recombinant vaccinia virus showed that TAP in human, monkey, and rabbit cells could be inhibited whereas mouse and rat TAP were unaffected (F. Momberg and H. Hengel, manuscript in preparation). 

Hengel H, Flohr T, Hammerling GJ, Koszinowski UH, Momburg F (1996) Human cytomegalovirus inhibits peptide translocation into the endoplasmic reticulum for MHC class 1 assembly. J Gen Virol 77 2287-2296... 

HCMV affects the cell surface expression of MHC class I molecules and therefore, reduces the antigen presentation for CD8 T lymphocytes (Barnes and Grundy 1992 Beersma et al. 1993 Hengel et al. 1995 Warren et al. 1994 Yamashita et al. 1993). HCMV-infected fibroblasts show a decrease in the peptide transport into the ER (Hengel et al. 1996). A temperature-sensitive mutant of HCMV, ts9, which lacks the genes US1-US15, had lost the capacity to interfere with MHC class I assembly and to inhibit the peptide translocation function of TAP (Hengel et al. 

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