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Friday XIII Adapt to the Highly Variable H-Region2 news and views brane lipids and its h-region has a helical proteins such as calmodulin9, or they are pre- conformation3. Enter the signal peptidase. sented to the immune system by molecules of Lys Its job: to skim the lumenal (or periplasmic) the major histocompatibility complex on the 145 COOH surface of the membrane, looking surface of the cell10. So, some signal peptides Ser 90 NH O H 2 H2N for suitably exposed signal-peptide cleavage probably have a second signalling function, Periplasm -1 COOH sites. Paetzel and colleagues’ structure of the distinct from their role in targeting. c -3 periplasmic domain of the E. coli enzyme1 We are experiencing a new wave of struc- tells us how this is accomplished. tural and biochemical work on protein tar- h First, an extended hydrophobic patch geting, which is finally showing us the int8i- n surrounds the active site, suggesting that this mate details of the life and death of signal Cytoplasm + + part of the enzyme is immersed in the outer peptides and the machineries that they put in N leaflet of the lipid bilayer. Second, the struc- motion. The key is the h-region — a simple ture of the active site readily explains the stretch of about ten hydrophobic residues Figure 1 The signal peptidase of Escherichia coli, requirement for small residues such as ala- that primes the SRP, unlocks the translocon the structure of which has been solved by Paetzel nine in positions 11 and 13, upstream of and positions the signal peptide for cleavage. et al.1. Two amino-terminal transmembrane the cleavage site, and also shows that the The messenger is the message. helices anchor the protein in the inner c-region must be in an extended confor- Gunnar von Heijne is in the Department of membrane, and the catalytic carboxy-terminal mation. The h-region thus, presumably, Biochemistry, Arrhenius Laboratories, Stockholm domain is partly immersed in the outer leaflet of positions the c-region near the lipid head- University, S-106 91 Stockholm, Sweden. the bilayer. Serine-90 (Ser 90) is the acylating groups, within reach of the signal peptidase. e-mail: [email protected] nucleophile and lysine-145 (Lys 145) acts as the This may also explain why signal peptidase 1. Paetzel, M., Dalbey, R. E. & Strynadka, N. C. J. Nature 396, general base in both the acylation and does not cleave transmembrane helices in 186–190 (1998). 2. Keenan, R. J., Freymann, D. M., Walter, P. & Stroud, R. M. Cell deacylation steps of catalysis. Small residues in integral membrane proteins, or signal pep- 94, 181–191 (1998). 8 positions 11 and 13 in the signal peptide bind tides with artificially lengthened h-regions . 3. Plath, K., Mothes, W., Wilkinson, B. M., Stirling, C. J. & to the S1 and S3 specificity pockets in the Such helices generally extend across the lipid Rapoport, T. A. Cell 94, 795–807 (1998). 4. Mothes, W., Jungnickel, B., Brunner, J. & Rapoport, T. A. enzyme. The h-region is helical, whereas the c- head-group region, so they do not present J. Cell Biol. 142, 355–364 (1998). region must be in an extended conformation to the required extended conformation. 5. Hamman, B. D., Hendershot, L. M. & Johnson, A. E. Cell 92, be accessible for cleavage. This is where the story could end — the 747–758 (1998). 6. Beckmann, R. et al. Science 278, 2123–2126 (1997). last mopping up is taken care of by various 7. Duong, F., Eichler, J., Price, A., Rice Leonard, M. & Wickner, W. some of these interactions become apparent. oligopeptidases, which digest the signal pep- Cell 91, 567–573 (1997). As the signal peptide emerges from the tide into free amino acids. But biology would 8. Nilsson, I., Whitley, P. & von Heijne, G. J. Cell Biol. 126, ribosome, it is first recognized by a ribonu- not be so interesting if it didn’t always come 1127–1132 (1994). 9. Martoglio, B., Graf, R. & Dobberstein, B. EMBO J. 16, cleoprotein complex, the signal recognition up with the unexpected. Certain signal pep- 6636–6645 (1997). particle (SRP). The subunit that binds the tides leak back into the cell where they bind to 10.Braud, V. M. et al. Nature 391, 795–799 (1998). signal peptide has a hydrophobic surface Chronology groove lined by flexible methionine side chains, and it seems perfectly designed to Friday XIII adapt to the highly variable h-region2. By virtue of its affinity for the membrane- This is the Friday the Thirteenth Club, TY bound SRP receptor, the SRP ensures that meeting in Paris in 1930 to dance the nascent protein is delivered to the underneath a ladder and carry open ON GET T translocon. Here, the signal peptide is scruti- umbrellas indoors. Being a rational reader HUL nized a second time, and it is eventually of Nature, you surely applaud this inserted in a lipid-exposed location between contemptuous attitude towards two transmembrane helices of the Sec61a superstition, so you won’t be at all protein3,4. In the ER translocon, this inser- concerned by the following sinister tale. tion step correlates with the establishment of In 1582, Pope Gregory XIII introduced a tight seal between the ribosome and the a new calendar to replace the old Julian translocation channel5. As seen by electron system, whose inaccuracies had made microscopy6, the nascent chain runs in a Easter slip slowly through the seasons. To closed, continuous tunnel from the riboso- bring the festivals back to their old mal P-site through the large ribosomal sub- positions, ten days disappeared from unit and then through the translocation October 1582. Some people thought the channel, finally emerging in the lumen of the days were being stolen from them. ER. In Escherichia coli, where proteins are But rebuilding and resetting the translocated after they have dissociated from calendar had a more subtle effect. The resorting to mathematics” (Spectrum the ribosome, the SecA protein seals the Gregorian cycle of 400 years contains October, 66; 1998). His table shows for channel from the cytoplasmic side and helps exactly 20,871 weeks, and hidden in the example that there are 688 Friday-the- move the nascent chain through the translo- calendar’s machinery is a bias towards thirteenths every 400 years, but only 684 con7. An X-ray structure of the SecA protein certain days of the week landing on certain Thursdays; and a month (like a week) is has been shown at meetings, but so far has dates in the month. The 13th is more likely most likely to begin on a Sunday. not been published. to be a Friday than any other day (Brown, Did the Friday the Thirteenth Club At this point, the signal peptide spans the B. H. Amer. Math. Monthly 40, 607; 1933). know of their good fortune in having these membrane with its carboxy-terminal end Bernard Yallop now points out that extra opportunities to carouse? I only hope facing the ER lumen (or, in E. coli, the with a personal computer it is possible to they didn’t meet a sticky end before finding periplasm). Although still associated with look for such peculiarities “without out. Stephen Battersby the translocon, it is also exposed to mem- NATURE | VOL 396 | 12 NOVEMBER 1998 | www.nature.com Nature © Macmillan Publishers Ltd 1998 113.
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