Biophys J, November 2000, p. 2754-2760, Vol. 79, No. 5

Serine and Threonine Residues Bend -Helices in the ₁ = g Conformation

Juan A. Ballesteros,^* Xavier Deupi,^* Mireia Olivella,^* Eric E. J. Haaksma, and Leonardo Pardo^*

 ^*Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain;  Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029 USA; and  Department of Chemistry, Boehringer Ingelheim Pharma KG, 88400 Biberach a.d. Riss, Germany

The relationship between the Ser, Thr, and Cys side-chain conformation (₁ = g, t, g⁺) and the main-chain conformation ( and  angles) has been studied in a selection of protein structures that contain -helices. The statistical results show that the g conformation of both Ser and Thr residues decreases their  angles and increases their  angles relative to Ala, used as a control. The additional hydrogen bond formed between the O atom of Ser and Thr and the i-3 or i-4 peptide carbonyl oxygen induces or stabilizes a bending angle in the helix 3-4° larger than for Ala. This is of particular significance for membrane proteins. Incorporation of this small bending angle in the transmembrane -helix at one side of the cell membrane results in a significant displacement of the residues located at the other side of the membrane. We hypothesize that local alterations of the rotamer configurations of these Ser and Thr residues may result in significant conformational changes across transmembrane helices, and thus participate in the molecular mechanisms underlying transmembrane signaling. This finding has provided the structural basis to understand the experimentally observed influence of Ser residues on the conformational equilibrium between inactive and active states of the receptor, in the neurotransmitter subfamily of G protein-coupled receptors.

Biophys J, November 2000, p. 2754-2760, Vol. 79, No. 5
© 2000 by the Biophysical Society   0006-3495/00/11/2754/07  $2.00

This article has been cited by other articles:

				R. A. Artigas, A. Gonzalez, E. Riquelme, C. A. Carvajal, A. Cattani, A. Martinez-Aguayo, A. M. Kalergis, T. Perez-Acle, and C. E. Fardella A Novel Adrenocorticotropin Receptor Mutation Alters Its Structure and Function, Causing Familial Glucocorticoid Deficiency J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3097 - 3105. [Abstract] [Full Text] [PDF]

				S. W. Gan, L. Ng, X. Lin, X. Gong, and J. Torres Structure and ion channel activity of the human respiratory syncytial virus (hRSV) small hydrophobic protein transmembrane domain Protein Sci., May 1, 2008; 17(5): 813 - 820. [Abstract] [Full Text] [PDF]

				P. Targett-Adams, T. Schaller, G. Hope, R. E. Lanford, S. M. Lemon, A. Martin, and J. McLauchlan Signal Peptide Peptidase Cleavage of GB Virus B Core Protein Is Required for Productive Infection in Vivo J. Biol. Chem., September 29, 2006; 281(39): 29221 - 29227. [Abstract] [Full Text] [PDF]

				S. M. Waters, R. M. Brodbeck, J. Steflik, J. Yu, C. Baltazar, A. E. Peck, D. Severance, L. Y. Zhang, K. Currie, B. L. Chenard, et al. Molecular Characterization of the Gerbil C5a Receptor and Identification of a Transmembrane Domain V Amino Acid That Is Crucial for Small Molecule Antagonist Interaction J. Biol. Chem., December 9, 2005; 280(49): 40617 - 40623. [Abstract] [Full Text] [PDF]

				O. Kinclova-Zimmermannova, M. Zavrel, and H. Sychrova Identification of Conserved Prolyl Residue Important for Transport Activity and the Substrate Specificity Range of Yeast Plasma Membrane Na+/H+ Antiporters J. Biol. Chem., August 26, 2005; 280(34): 30638 - 30647. [Abstract] [Full Text] [PDF]

				R. Zhang, D. P. Hurst, J. Barnett-Norris, P. H. Reggio, and Z.-H. Song Cysteine 2.59(89) in the Second Transmembrane Domain of Human CB2 Receptor Is Accessible within the Ligand Binding Crevice: Evidence for Possible CB2 Deviation from a Rhodopsin Template Mol. Pharmacol., July 1, 2005; 68(1): 69 - 83. [Abstract] [Full Text] [PDF]

				C. Ambrosio, P. Molinari, F. Fanelli, Y. Chuman, M. Sbraccia, O. Ugur, and T. Costa Different Structural Requirements for the Constitutive and the Agonist-induced Activities of the {beta}2-Adrenergic Receptor J. Biol. Chem., June 24, 2005; 280(25): 23464 - 23474. [Abstract] [Full Text] [PDF]

				R. Del Carmine, P. Molinari, M. Sbraccia, C. Ambrosio, and T. Costa "Induced-Fit" Mechanism for Catecholamine Binding to the {beta}2-Adrenergic Receptor Mol. Pharmacol., August 1, 2004; 66(2): 356 - 363. [Abstract] [Full Text] [PDF]

				X. Deupi, M. Olivella, C. Govaerts, J. A. Ballesteros, M. Campillo, and L. Pardo Ser and Thr Residues Modulate the Conformation of Pro-Kinked Transmembrane {alpha}-Helices Biophys. J., January 1, 2004; 86(1): 105 - 115. [Abstract] [Full Text] [PDF]

				C. Govaerts, A. Bondue, J.-Y. Springael, M. Olivella, X. Deupi, E. Le Poul, S. J. Wodak, M. Parmentier, L. Pardo, and C. Blanpain Activation of CCR5 by Chemokines Involves an Aromatic Cluster between Transmembrane Helices 2 and 3 J. Biol. Chem., January 10, 2003; 278(3): 1892 - 1903. [Abstract] [Full Text] [PDF]

				L. Shi, G. Liapakis, R. Xu, F. Guarnieri, J. A. Ballesteros, and J. A. Javitch beta 2 Adrenergic Receptor Activation. MODULATION OF THE PROLINE KINK IN TRANSMEMBRANE 6 BY A ROTAMER TOGGLE SWITCH J. Biol. Chem., October 18, 2002; 277(43): 40989 - 40996. [Abstract] [Full Text] [PDF]

				M. L. Lopez-Rodriguez, B. Vicente, X. Deupi, S. Barrondo, M. Olivella, M. J. Morcillo, B. Behamu, J. A. Ballesteros, J. Salles, and L. Pardo Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine1a Receptor Ligands to Explore the Three-Dimensional Structure of the Receptor Mol. Pharmacol., July 1, 2002; 62(1): 15 - 21. [Abstract] [Full Text] [PDF]

				M. Olivella, X. Deupi, C. Govaerts, and L. Pardo Influence of the Environment in the Conformation of alpha -Helices Studied by Protein Database Search and Molecular Dynamics Simulations Biophys. J., June 1, 2002; 82(6): 3207 - 3213. [Abstract] [Full Text] [PDF]

				A. Senes, I. Ubarretxena-Belandia, and D. M. Engelman The Calpha ---H{middle dot}{middle dot}{middle dot}O hydrogen bond: A determinant of stability and specificity in transmembrane helix interactions PNAS, July 31, 2001; 98(16): 9056 - 9061. [Abstract] [Full Text] [PDF]

				J. A. Ballesteros, L. Shi, and J. A. Javitch Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors Mol. Pharmacol., July 1, 2001; 60(1): 1 - 19. [Abstract] [Full Text]

				C. Govaerts, C. Blanpain, X. Deupi, S. Ballet, J. A. Ballesteros, S. J. Wodak, G. Vassart, L. Pardo, and M. Parmentier The TXP Motif in the Second Transmembrane Helix of CCR5. A STRUCTURAL DETERMINANT OF CHEMOKINE-INDUCED ACTIVATION J. Biol. Chem., April 13, 2001; 276(16): 13217 - 13225. [Abstract] [Full Text] [PDF]

				S. Preiss, A. Argentaro, A. Clayton, A. John, D. A. Jans, T. Ogata, T. Nagai, I. Barroso, A. J. Schafer, and V. R. Harley Compound Effects of Point Mutations Causing Campomelic Dysplasia/Autosomal Sex Reversal upon SOX9 Structure, Nuclear Transport, DNA Binding, and Transcriptional Activation J. Biol. Chem., July 20, 2001; 276(30): 27864 - 27872. [Abstract] [Full Text] [PDF]