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A Prolactin-Releasing Peptide in the Brain Engineering Cyclophilin Into A letters to nature 5. Bartlett, P. A. & Satake, K. Does dehydroquinate synthase synthesize dehydroquinate? J. Am. Chem. Soc. 110, 1628–1630 (1988). 6. Lambert, J. M., Boocock, M. R. & Coggins, J. R. The 3-dehydroquinate synthase activity of the pentafunctional arom enzyme complex of Neurospora crassa is Zn2+ dependent. Biochem. J. 226, 817– addendum 829 (1985). 7. Montchamp, J.-L. & Frost, J. W. Cyclohexenyl and cyclohexylidene inhibitors of 3-dehydroquinate synthase: Active site interactions relevant to enzyme mechanisms and inhibitor design. J. Am. Chem. Soc. 119, 7645–7653 (1997). 8. Bentley, R. The shikimate pathway—a metabolic tree with many branches. Crit. Rev. Biochem. Mol. A prolactin-releasing Biol. 25, 307–384 (1990). 9. Kishore, G. M. & Shah, D. M. Amino acid biosynthesis inhibitors as herbicides. Annu. Rev. Biochem. 57, 27–63 (1988). peptide in the brain 10. Pittard, A. J. 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SCOP-A structural classification of proteins proprolactin-releasing peptide; AB015418, Rattus norvegicus database for the investigation of sequences and structures. J. Mol. Biol. 247, 536–540 (1995). mRNA for preproprolactin-releasing peptide; AB015419, Homo 19. Eklund, H. et al. Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 A˚ resolution. sapiens mRNA for preproprolactin-releasing peptide. M J. Mol. Biol. 102, 27–59 (1976). 20. Eklund, H. et al. Structure of the triclinic ternary complex of horse liver alcohol dehydrogenase at 2.9 A˚ resolution. J. Mol. Biol. 146, 561–587 (1981). 21. Van Den Hombergh, J. P. T. W., Moore, J. D., Charles, I. G. & Hawkins, A. R. Overproduction in Escherichia coli of the dehydroquinate synthase domain of the Aspergillus nidulans pentafunctional AROM protein. Biochem. J. 284, 861–867 (1992). 22. Moore, J. D., Coggins, J. R., Virden, R. & Hawkins, A. R. Efficient independent activity of a correction monomeric, monofunctional dehydroquinate synthase derived from the N-terminus of the penta- functional AROM protein of Aspergillus nidulans. Biochem. J. 301, 297–304 (1994). 23. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Meth. Enzymol. 276, 307–326 (1996). 24. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994). Engineering cyclophilin 25. Terwilliger, T. C., Kim, S.-H. & Eisenberg, D. Generalised method of determining heavy atom positions using the difference Patterson function. Acta Crystallogr. A 43, 1–5 (1987). into a proline-specific 26. Jones, T. A., Zou, J.-Y., Cowan, S.W. & Kjeldgaard, M. Improved methods for building protein models in electron-density and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991). 27. Tronrud, D. E., The TNT Refinement Package Manual, 1–191, Oregon State Board of Higher endopeptidase Education (1993). 28. Brunger, A. T. Free R-value—a novel statistical quantity for assessing the accuracy of crystal Eric Que´ me´ neur, Mireille Moutiez, structures. Nature 355, 472–475 (1992). Jean-Baptiste Charbonnier & Andre´ Me´ nez 29. Esnouf, R. M. An extensively modified version of Molscript that includes greatly enhanced coloring capabilities. J. Mol. Graph. Model. 15, 132 (1997). Nature 391, 301–304 (1998) Acknowledgements. We thank the support staff at the Synchrotron Radiation Source at Daresbury .................................................................................................................................. Laboratory, UK, for assistance; D. R. Swatman, F.T.F. Tsai, R. R. Patel and Y. S. Li for technical assistance; The efficiency value (kcat/Km) of cyproase 1 is equal to G. G. Dodson for support and encouragement; K. Henrick, S. Gamblin, M. Hirschberg, J. O. Baum, : 3 4 2 1 2 1 : 3 4 2 1 2 1 W. Taylor and J. D. Moore for discussion; and P. Bartlett for helpful comments. This work was supported 0 2 10 M s , and not to 0 7 10 M s as published. by BBSRC. E.P.C. was supported by the UK MRC and K.A.B. received a BBSRC Advanced Fellowship. Also, the histidine at residue 104 titrates with a pK equal to : 6 : : 6 : Correspondence and requests for materials should be addressed to K.A.B. (e-mail: [email protected]). 6 47 0 16 and 6 74 0 15 when measuring Kcat and the kcat/Km, Coordinates have been deposited with the Brookhaven Databank under accession number 1dqs. respectively, and not to 6:74 6 0:16 and 6:74 6 0:15. M Nature © Macmillan Publishers Ltd 1998 302 NATURE | VOL 394 | 16 JULY 1998 letters to nature = 2 : 2 2 : 2 10. Mel, B. Information processing in dendritic trees. Neural Comp. 6, 1031–1085 (1994). V 5Þ V 6}, and, in mV, V 1 ¼ 42 5, V 2 ¼ 1, V 3 ¼ 43 0, V 4 ¼ 4, ¼ 2 : ¼ 11. Segev, I. in The Handbook of Brain Theory and Neural Networks (ed. Arbib, M.) 282–289 (MIT Press, V 5 60 0, and V 6 64. Simulation results were obtained by numerical Cambridge, MA, 1995). integration of differential equations over 10 s. 12. Pinsky, P. F. & Rinzel, J. Intrinsic and network rhythmogenesis in a reduced Traub model for CA3 Bipolar-neuron model. See Fig. 2a. The soma was the same as in the point- neurons. J. Comput. Neurosci. 1, 39–40 (1994). m 13. Mainen, Z. F. & Sejnowski, T. J. Influence of dendritic structure on firing pattern in model neocortical neuron model (20 m diameter, Rsoma ¼ 135 MQ); the dendritic diameter was neurons. Nature 382, 363–366 (1996). either 4 mm (thick dendrites) or 2 mm (thin dendrites), with axial resistivity 14. Softky, W. R. & Koch, C. The highly irregular firing of cortical cells in inconsistent with temporal ¼ ¼ ; 2 integration of random EPSPs. J. Neurosci. 13, 334–350 (1993). Ri 200 Q cm and membrane resistance Rm 1 700 Q cm . For a dendrite of 15. Borst, A. & Egelhaaf, M. Dendritic processing of synaptic information by sensory interneurons. Trends diameter 4 mm, l ¼ 290 mm, whereas for a dendrite of diameter 2 mm, Neurosci. 17, 257–263 (1994). l ¼ 200 mm. Parameters were based on recordings from chicken coincidence 16. Borst, A. How do nerve cells compute? Dendritic integration in fly visual neurons. Acta Physiol. Scand. 157, 403–407 (1996). 20 8 detectors . Dendrites were modelled by 0.05-l-connected compartments and 17. Haag, J. & Borst, A. Amplification of high-frequency synaptic inputs by active dendritic membrane had either active membrane (identical to the point neuron) or passive processes. Nature 379, 639–641 (1996). 18. Parks, T. N. & Rubel, E. W. Organization of the projections from n. magnocellularis to n. laminaris. membrane (voltage-dependent conductances fixed to their resting values). J. Comp. Neurol. 180, 439–448 (1975). Because synaptic inputs arrived at the cell in every cycle, it was insufficient to 19. Reyes, A. D., Rubel, E. W. & Spain, W. J. Membrane properties underlying the firing of neurons in the use a simple threshold function to recognize action potentials in the somatic avian cochlear nucleus. J. Neurosci. 14, 5352–5364 (1994). 20. Reyes, A. D., Rubel, E. W. & Spain, W. J. In vitro analysis of optimal stimuli for phase-locking and time- response. We therefore added a long axon with a higher density of voltage- delayed modulation of firing in avian nucleus laminaris neurons. J. Neurosci. 16, 993–1000 (1996). dependent conductances. We counted only action potentials that propagated. 21. Zhang, S. & Trussell,L. O. A characterization of excitatory postsynaptic potentials in the avian nucleus magnocellularis. J. Neurophysiol. 72, 705–718 (1994). Synaptic-input model. See Fig. 2b. For every input train, at every stimulus 22. Manis, P. B. & Marx, S. O. Outward currents in isolated ventral cochlear nucleus neurons. J. Neurosci. cycle, the probability of an input arriving was defined as fpre/fstim, where fstim was 11, 2865–2880 (1991). 23. Agmon-Snir, H., Carr, C. E. & Rinzel, J. A simple biophysical model for analyzing phase-locking and the stimulus frequency and fpre (<fstim) was the average spike rate of the input coincidence detection inauditory neurons. Soc. Neurosci. Abstr. 22, 402 (1996). 27 train. f pre ¼ 350 Hz for all stimulus frequencies . The stimulus cycles were 24.
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