Abstract
Neurophysins I and II (NPI and NPII) act in the neurosecretory granules as carrier proteinsfor the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The NPI/OTfunctional unit, believed to be an (NPI/OT)2 heterotetramer, was modeled using low-resolution structure information, viz. the Cα carbon atom coordinates of the homologousNPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Databank) as a template. Itsall-atom representation was obtained using standard modeling tools available within theINSIGHT/Biopolymer modules supplied by Biosym Technologies Inc. A conformation of theNPI-bound OT, similar to that recently proposed in a transfer NOE experiment, was dockedinto the ligand-binding site by a superposition of its Cys1-Tyr2 fragment onto the equivalentportion of the dipeptide in the template. The starting complex for the initial refinements wasprepared by two alternative strategies, termed Model I and Model II, each ending with a∼100 ps molecular dynamics (MD) simulation in water using the AMBER 4.1 force field. The freehomodimer NPI2 was obtained by removal of the two OT subunits from their sites, followedby a similar structure refinement. The use of Model I, consisting of a constrained simulatedannealing, resulted in a structure remarkably similar to both the NPII/dipeptide complex anda recently published solid-state structure of the NPII/OT complex. Thus, Model I isrecommended as the method of choice for the preparation of the starting all-atom data forMD. The MD simulations indicate that, both in the homodimer and in the heterotetramer, the310-helices demonstrate an increased mobility relative to the remaining body of the protein.Also, the C-terminal domains in the NPI2 homodimer are more mobile than the N-terminalones. Finally, a distinct intermonomer interaction is identified, concentrated around its mostprominent, although not unique, contribution provided by an H-bond from Ser25Oγ in one NPI unit to Glu81 Oε in the other unit. This interaction is present in the heterotetramer(NPI/OT)2 and absent or weak in the NPI2 homodimer. We speculate that this interaction,along with the increased mobility of the 310-helices and the carboxy domains, may contributeto the allosteric communication between ligand binding and NPI dimerization.
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References
Dreifuss, J.J., Ann. New York Acad. Sci., 248 (1975) 184.
Brownstein, M.J., Russell, J.T. and Ganier, H., Science, 207 (1980) 373.
Land, H., Schutz, G., Schmale, H. and Richter, D., Nature, 295 (1982) 299.
Breslow, E. and Burman, S., Adv. Enzymol., 63 (1990) 1.
Breslow, E. and Walter, R., Mol. Pharmacol., 8 (1972) 5.
Breslow, E., Annu. Rev. Biochem., 48 (1978) 251.
Menendez-Botet, C. and Breslow, E., Biochemistry, 14 (1975) 3825.
Chaiken, I.M., Randolph, R.E. and Taylor, H.C., Ann. New York Acad. Sci., 248 (1975) 442.
Kanmera, T. and Chaiken, I.M., J. Biol. Chem., 260 (1985) 8474.
Ando, S., McPhie, P. and Chaiken, I.M., J. Biol. Chem., 262 (1987) 12962.
Huang, H.B. and Breslow, E., J. Biol. Chem., 267 (1992) 6750.
Chen, L., Rose, J.P., Breslow, E., Yang, D., Chang, W.-E., Furey Jr., W.F., Sax, M. and Wang, B.-C., Proc. Natl. Acad. Sci. USA, 88 (1991) 4240.
Rose, J.P., Wu, Ch.-K., Hsiao, Ch.-D., Breslow, E. and Wang, B.-C., Nat. Struct. Biol., 3 (1996) 163.
Kaźmierkiewicz, R., Czaplewski, C., Lammek, B., Ciarkowski, J. and Lesyng, B., J. Mol. Model., 1 (1995) 135.
Bernstein, F.C., Koetzle, T.F., Williams, G.J., Meyer, E.E.J., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tsanumi, M., J. Mol. Biol., 112 (1977) 535.
SYBYL, v. 6.1, Tripos Inc., St. Louis, MO, U.S.A., 1994.
Lippens, G., Hallenga, K., Van Belle, S., Wodak, S.J., Nirmala, N.R., Hill, P., Russel, K.C., Smith, D.D. and Hruby, V.J., Biochemistry, 32 (1993) 9423.
Breslow, E., Sardana, V., Deeb, R., Barbar, E. and Peyton, D.H., Biochemistry, 34 (1995) 2137.
AMBER 4.1, Pearlman, D.A., Case, D.A., Caldwell, J.W., Ross, W.S., Cheatham III, T.E., Ferguson, D.M., Seibel, G.L., Singh, U.C., Weiner, P.K. and Kollman, P.A., University of California, San Francisco, CA, U.S.A., 1995.
Jorgensen, W.L., Chandresekhar, J., Madura, J., Impey, R. and Klein, M., J. Chem. Phys., 79 (1983) 926.
Berendsen, H.J.C., Postma, J.P.M., van Gunsteren, W.F., DiNola, A. and Haak, J.R., J. Chem. Phys., 81 (1984) 3684.
Kraulis, P., J. Appl. Crystallogr., 24 (1991) 946.
RasMol, v. 2.6, Molecular Visualisation Program, Sayle, R., Glaxo Wellcome Research and Development, Stevenage, Hertfordshire, U.K.
INSIGHT/DISCOVER, Biosym Technologies Inc., San Diego, CA, U.S.A., 1994.
Kaźmierkiewicz, R. et al., QSAR, (1997) in press.
Breslow, E., In Gross, P., Richter, G. and Robertson, G.L. (Eds.) Vasopressin, John Libbey Eurotext, Paris, France, 1993, pp. 143–155.
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Kazmierkiewicz, R., Czaplewski, C., Lammek, B. et al. Molecular modeling of the neurophysin I/oxytocin complex. J Comput Aided Mol Des 11, 9–20 (1997). https://doi.org/10.1023/A:1008063025493
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DOI: https://doi.org/10.1023/A:1008063025493