Investigating the conformational determinants of the activity of 26RFa: an orexigenic neuropeptide
2016
26RFa, a RFamide neuropeptide, is the ligand of the G-protein-coupled-receptor GPR103 and the system 26RFa/GPR103 is involved in different biological activities, among which the main one is an orexigenic activity in the control of food intake.[1,2] Structure-Activity Relationship studies on 26RFa truncated fragments indicated that the deletion of the first residues does not markedly alter the binding (IC50: 26RFa=3.2nM; 26RFa8-26=49nM)[3] and the biological activity (EC50: 26RFa=10.4 nM; 26RFa10-26=37.5nM) while the suppression of additional residues provokes more important effects (IC50: 26RFa17-26=220nM; 26RFa19-26=2900nM; 26RFa20-26 > 10 000 nM; EC50: 26RFa13-26=95.3nM; 26RFa16-26=237nM; 26RFa20-26=739nM).[3,4]
In order to explain these differences, we determined the solution structures of 26RFa and several N-terminal truncated fragments (26RFa7-26, 26RFa11-26, 26RFa13-26 and 26RFa20-26) in the presence of DPC micelles, a membrane mimetic medium. In this medium, 26RFa possesses an -helix (P4-K19), followed by interlaced type I -turns in the C-terminal region (F22-F26). Deletion of N-terminal residues led to destabilization (26RFa11-26) then loss of the helical conformation (26RFa13-26), but the C-terminal structuration is conserved. In 26RFa20-26, the structure of the region (F22-F26) is altered, the nature of the turns being modified.
These results show that (i) a correct 26RFa C-terminal structuration is necessary for GPR103 binding and activation; (ii) part of the N-terminal region is required to maintain this C-terminal conformation, but the entire helix is not necessary; (iii) both part of the helix and a correct C-terminal structure are necessary for 26RFa activity.
Acknowledgments: This work was supported by ERDF funding through the IS:CE-Chem project and Interreg IV A France-(Channel)-England programme. The authors also thank the CRUNCh network for its financial support and the CRIHAN for molecular modelling facilities.
References
1. J.C. do Rego J. Leprince, N. Chartrel, H. Vaudry, J. Costentin, Peptides (2006), 27, 2715.
2. S. Takayasu, T. Sakurai, S. Iwasaki, H. Teranishi, A. Yamanaka, S.C. Williams, H. Iguchi, Y.I. Kawasawa, Y. Ikeda, I. Sakakibara, K. Ohno, R.X. Ioka, S. Murakami, N. Dohmae, J. Xie, T. Suda, T. Motoike, T. Ohuchi, M. Yanagisawa, J. Sakai, Proc. Natl. Acad. Sci. U S A. (2006), 103, 7438.
3. S.Fukusumi, H. Yoshida, R. Fuji, M. Maruyama, H. Komatsu, Y. Habata, Y. Shintani, S. Hinuma, M. Fujino M, J. Biol. Chem. (2003), 278, 46387.
4. O. Le Marec, C. Neveu, B. Lefranc, C. Dubessy, J.A. Boutin, J.C. Do-Rego JC, J. Costentin, M.C. Tonon, M. Tena-Sempere, H. Vaudry, J. Leprince, J. Med. Chem. (2011), 54, 4806.
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