Peptides in membranes: Lipid-induced secondary structure of substance P

Woolley, G. Andrew; Deber, Charles M.

doi:10.1002/bip.360260012

Cited by 77 publications

(89 citation statements)

References 34 publications

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“…Even the differences between the anionic interface (in SDS) and the zwitterionic interface (in DPC) do not cause significant differences in the conformation of the bound peptides. This result is consistent with previous studies on SP 11,12 and other peptides, 18 which suggested structures of peptides in the presence of lipids are independent of lipid headgroup type. The differences in the surface charge do affect the partition of SP and [Tyr 8 ]SP, as well as NKA and [Tyr 0 ]NKA, in these micelles as discussed in an earlier section.…”

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confidence: 95%

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The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

Gao

Wong

1999

Biopolymers

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supporting

confidence: 95%

“…14 SP has a random structure in aqueous solutions, but exhibits a partial helical structure in the presence of phospholipid bilayers, 7,10 lipid micelles, 11,12 and sodium dodecylsulfate (SDS) micelles. 12,13 NKA has been studied by nmr in water and in methanol, 15 in 28% trifluoroethanol (TFE)/water mixture, 16 and in 50 mM SDS micelles.…”

Section: Introductionmentioning

confidence: 99%

The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

Gao

Wong

1999

Biopolymers

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“…The conservation of these residues has led to the speculation that the Asn 23 -Phe 25 region of the NK-1R may play an important structural role in positioning or stabilizing the tertiary structure of the N terminus. Indeed, in the resulting model, these residues are at the point where the N terminus bends; the residues preceding Asn 23 are projecting over the seven-TM core, whereas the residues after Phe 25 18 ) would certainly play an important role in the proposed folding of the N terminus over the ligand in the central core of the seven transmembrane helices. The presence of the carbohydrate side chain residues does not appear to be necessary for ligand binding to the NK-1R as determined independently by photoaffinity labeling experiments (38) and receptor mutational analysis (10).…”

Section: Discussionmentioning

confidence: 99%

“…The ligand⅐receptor complexes that best fulfilled the experimental restraints were utilized as starting structures for the following simulations. Based on numerous NMR studies of SP, an ␣-helix in the center of the sequence, from Gln 4 to Phe 8 , was assumed (25)(26)(27)(28)(29) …”

Section: Methodsmentioning

confidence: 99%

Molecular Characterization of the Substance P·Neurokinin-1 Receptor Complex

Pellegrini

Bremer

Ulfers

et al. 2001

Journal of Biological Chemistry

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1 is a member of the G protein-coupled receptor family of integral membrane proteins activated by the tachykinin peptide hormones substance P (SP) and neurokinin A. Over the years, a number of different methods have been employed to characterize the NK-1R and the mode in which it interacts with these peptide ligands as well as with a number of non-peptide antagonists that target the NK-1R. Based on site-directed mutagenesis, fluorescence experiments, and engineering of zinc-binding pockets, a number of residues involved in the binding of the non-peptide antagonists has been identified (1-7). Most of these residues are located within the hydrophobic core formed by the seven transmembrane helices (TM), predominantly in the region of TM5 and TM6. Using these putative sites of ligand/receptor interaction and computational models of the receptor, insight into the mode of ligand binding of these antagonists has been developed (7-9).The development of a similar understanding of the binding of the peptide ligands SP and neurokinin A to the NK-1R has been much more challenging. Most of the residues identified as important for SP binding are in the N terminus or extracellular loops of the NK-1R (10 -12). These regions are not structurally characterized (in contrast to the bundle of transmembrane helices, homology modeling based on rhodopsin is not possible for the loops and termini); and therefore, molecular models have a much greater uncertainty associated with them.To address these issues, we have undertaken the structural characterization of the extracellular domains of the NK-1R (13). The experimentally based conformational preferences can then be incorporated into the model of the full-length receptor. Coupling these data with the identification of ligand/receptor contact points as determined by photoaffinity labeling provides unique insight into the interactions involved in the binding of SP to the NK-1R.Here we describe a model for the binding of SP to the NK-1R that incorporates all of the experimental data currently available. The model contains the structural features of the second extracellular loop (EC2) of the NK-1R as recently determined by high resolution NMR (13). The loop plays an important role in SP binding, as evidenced by previous photoaffinity studies (13)(14)(15)(16)(17). Both position 4 (Bpa 4 SP) and position 8 (Bpa 8 SP) of SP form covalent linkages with residues in EC2, Met 174 and Met 181 , respectively. As described in the accompanying article (17), a residue in EC2, between residues 173 and 177, is photoaffinity labeled by Bpa 3 SP. Interestingly, Bpa 3 SP also forms

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“…In addition, shifts are seen in the pK,s of peptide titratable protons at SDS micelle surfaces (Fernandez & Fromherz, 1977;Woolley & Deber, 1987;O'Neil & Sykes, 1989;Beschiaschvili & Seelig, 1992). The pK, shifts are attributed to the reduced dielectric at the micelle-solution interface and the potential caused by the charged lipid head groups (Fernandez & Fromherz, 1977).…”

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confidence: 99%

The orientation and dynamics of substance P in lipid environments

Keire

Kobayashi

1998

Protein Science

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The membrane-associated conformation of substance P (RPKPQQFFGLM-NH2) has been previously proposed to be the NKI-receptor-active conformation. In this work, NMR methods are applied to explore the orientation and dynamics of substance P at lipid surfaces for which the peptide's three-dimensional structure had been previously determined. Here the presence of dodecylphosphocholine (DPC) or sodium dodecylsulfate (SDS) micelles has been found to cause sequence specific changes in the acid-and base-catalyzed amide proton exchange rates relative to the solution state values. On binding of substance P to SDS micelles, the FFG portion showed the largest decreases in the base-catalyzed amide exchange rates. Similar sequence-specific changes in substance P are observed in the presence of DPC micelles, albeit at much weaker levels due to fast exchange between free and bound forms of the peptide. These differences are attributed to the location of the amide protons either in the surface double layer (via electrostatic effect) or inserted into the polar head group region of the micelles (via low dielectric). The sequence-specific effects of micelle association were also observed in the homonuclear nonselective spin-lattice relaxation time; these, in combination with spin-spin relaxation times, were used to calculate correlation times for the backbone amide protons. These data combined with paramagnetic broadening observations on peptide protons in the presence of spin-labeled lipids yield a detailed model of the interaction of substance P with lipid surfaces.Keywords: amide exchange; correlation times; dodecylphosphocholine; NMR; peptide-lipid interactions; sodium dodecylsulfate; substance P; TI and T2 relaxation Substance P (SP) is a member of the tachykinin family of neuropeptides and is widely distributed in both the central and peripheral nervous system of humans. Tachykinins, which are characterized by a common C-terminal tail (F-x-GLM-NH2 where x is F or V for mammals), are of biomedical interest because they have been shown to cause hypotension, contraction of smooth muscles, salivation, transmission of pain, and inflammation (Pernow, 1983). Ligands of SP receptors have potential as a novel class of anti-inflammatory or pain medication, and as a result, interest is high in the structural elements of the peptide that may control receptor activity and selectivity.The membrane-bound conformation of SP has been proposed to be the NK1 receptor active form (Schwyzer, 1995), and the three-dimensional structure of SP in the presence of Abbreviations: DPC, dodecylphosphocholine; RMSD, root-mean-square deviation; SDS, sodium dodecylsulfate; SP, substance P; 2D TOCSY, twodimensional total correlation spectroscopy. 1996). Both structures were similar, although fast exchange between free and bound forms was observed for SP with DPC micelles and predominantly bound characteristics were found for SP with SDS micelles.The three-dimensional SP structure at these lipid-membrane mimetics may represent either a receptor-bound co...

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Peptides in membranes: Lipid-induced secondary structure of substance P

Cited by 77 publications

References 34 publications

The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

The study of the conformation and interaction of two tachykinin peptides in membrane mimicking systems by NMR spectroscopy and pulsed field gradient diffusion

Molecular Characterization of the Substance P·Neurokinin-1 Receptor Complex

The orientation and dynamics of substance P in lipid environments

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